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Liu J, Yuan Q, Guo H, Guan H, Hong Z, Shang D. Deciphering drug resistance in gastric cancer: Potential mechanisms and future perspectives. Biomed Pharmacother 2024; 173:116310. [PMID: 38394851 DOI: 10.1016/j.biopha.2024.116310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 02/07/2024] [Accepted: 02/17/2024] [Indexed: 02/25/2024] Open
Abstract
Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa. The latest global cancer statistics show that GC ranks fifth in incidence and fourth in mortality among all cancers, posing a serious threat to public health. While early-stage GC is primarily treated through surgery, chemotherapy is the frontline option for advanced cases. Currently, commonly used chemotherapy regimens include FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine). However, with the widespread use of chemotherapy, an increasing number of cases of drug resistance have emerged. This article primarily explores the potential mechanisms of chemotherapy resistance in GC patients from five perspectives: cell death, tumor microenvironment, non-coding RNA, epigenetics, and epithelial-mesenchymal transition. Additionally, it proposes feasibility strategies to overcome drug resistance from four angles: cancer stem cells, tumor microenvironment, natural products, and combined therapy. The hope is that this article will provide guidance for researchers in the field and bring hope to more GC patients.
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Affiliation(s)
- Jiahua Liu
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qihang Yuan
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hui Guo
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hewen Guan
- First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Zhijun Hong
- First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Dong Shang
- First Affiliated Hospital of Dalian Medical University, Dalian, China.
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Scheck MK, Hofheinz RD, Lorenzen S. HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments. Cancers (Basel) 2024; 16:1336. [PMID: 38611014 PMCID: PMC11010911 DOI: 10.3390/cancers16071336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.
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Affiliation(s)
- Magdalena K. Scheck
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
| | - Ralf D. Hofheinz
- Mannheim Cancer Center, Universitätsklinikum Mannheim, 68167 Mannheim, Germany;
| | - Sylvie Lorenzen
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
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Zhao X, Xu Z, Meng B, Ren T, Wang X, Hou R, Li S, Ma W, Liu D, Zheng J, Shi M. Long noncoding RNA NONHSAT160169.1 promotes resistance via hsa-let-7c-3p/SOX2 axis in gastric cancer. Sci Rep 2023; 13:20858. [PMID: 38012281 PMCID: PMC10682003 DOI: 10.1038/s41598-023-47961-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 11/20/2023] [Indexed: 11/29/2023] Open
Abstract
In clinical trials involving patients with HER2 (ERBB2 receptor tyrosine kinase 2) positive gastric cancer, the efficacy of the HER2-targeted drug lapatinib has proven to be disappointingly poor. Under the persistent pressure exerted by targeted drug therapy, a subset of tumor cells exhibit acquired drug resistance through the activation of novel survival signaling cascades, alongside the proliferation of tumor cells that previously harbored mutations conferring resistance to the drug. This study was undertaken with the aim of elucidating in comprehensive detail the intricate mechanisms behind adaptive resistance and identifying novel therapeutic targets that hold promise in the development of effective lapatinib-based therapies for the specific subset of patients afflicted with gastric cancer. We have successfully established a gastric cancer cell line with acquired lapatinib resistance, designated as HGC-27-LR cells. Utilizing comprehensive coding and noncoding transcriptome sequencing analysis, we have identified key factors that regulate lapatinib resistance in HGC-27 cells. We have compellingly validated that among all the lncRNAs identified in HGC-27-LR cells, a novel lncRNA (long noncoding RNA) named NONHSAT160169.1 was found to be most notably upregulated following exposure to lapatinib treatment. The upregulation of NONHSAT160169.1 significantly augmented the migratory, invasive, and stemness capabilities of HGC-27-LR cells. Furthermore, we have delved into the mechanism by which NONHSAT160169.1 regulates lapatinib resistance. The findings have revealed that NONHSAT160169.1, which is induced by the p-STAT3 (signal transducer and activator of transcription 3) nuclear transport pathway, functions as a decoy that competitively interacts with hsa-let-7c-3p and thereby abrogates the inhibitory effect of hsa-let-7c-3p on SOX2 (SRY-box transcription factor 2) expression. Hence, our study has unveiled the NONHSAT160169.1/hsa-let-7c-3p/SOX2 signaling pathway as a novel and pivotal axis for comprehending and surmounting lapatinib resistance in the treatment of HER2-positive gastric cancer.
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Affiliation(s)
- Xuan Zhao
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Zijian Xu
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Bi Meng
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Tong Ren
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Xu Wang
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Rui Hou
- College of Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Sijin Li
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Wen Ma
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Dan Liu
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China.
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
| | - Junnian Zheng
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China.
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
| | - Ming Shi
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221002, Jiangsu, China.
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
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González-Rubio S, Salgado C, Manzaneda-González V, Muñoz-Úbeda M, Ahijado-Guzmán R, Natale P, Almendro-Vedia VG, Junquera E, Barcina JO, Ferrer I, Guerrero-Martínez A, Paz-Ares L, López-Montero I. Tunable gold nanorod/NAO conjugates for selective drug delivery in mitochondria-targeted cancer therapy. NANOSCALE 2022; 14:8028-8040. [PMID: 35616261 DOI: 10.1039/d2nr02353a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Nonyl acridine orange (NAO) is a lipophilic and positively charged molecule widely used as a mitochondrial fluorescent probe. NAO is cytotoxic at micromolar concentration and might be potentially used as a mitochondria-targeted drug for cancer therapy. However, the use of NAO under in vivo conditions would be compromised by the unspecific interactions with off-target cells and negatively charged proteins present in the bloodstream. To tackle this limitation, we have synthesized NAO analogues carrying an imidazole group for their specific binding to nitrilotriacetic (NTA) functionalized gold nanorods (AuNRs). We demonstrate that AuNRs provide 104 binding sites and a controlled delivery under acidic conditions. Upon incubation with mouse embryonic fibroblasts, the endosomal acidic environment releases the NAO analogues from AuNRs, as visualized through the staining of the mitochondrial network. The addition of the monoclonal antibody Cetuximab to the conjugates enhanced their uptake within lung cancer cells and the conjugates were cytotoxic at subnanomolar concentrations (c50 ≈ 0.06 nM). Moreover, the specific interactions of Cetuximab with the epidermal growth factor receptor (EGFR) provided a specific targeting of EGFR-expressing lung cancer cells. After intravenous administration in patient-derived xenografts (PDX) mouse models, the conjugates reduced the progression of EGFR-positive tumors. Overall, the NAO-AuNRs provide a promising strategy to realize membrane mitochondria-targeted conjugates for lung cancer therapy.
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Affiliation(s)
- Sergio González-Rubio
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
- Instituto de Investigación Hospital Doce de Octubre (imas12), Avenida de Córdoba s/n, 28041 Madrid, Spain.
| | - Cástor Salgado
- Departamento Química Orgánica, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
| | - Vanesa Manzaneda-González
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
| | - Mónica Muñoz-Úbeda
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
- Instituto de Investigación Hospital Doce de Octubre (imas12), Avenida de Córdoba s/n, 28041 Madrid, Spain.
| | - Rubén Ahijado-Guzmán
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
| | - Paolo Natale
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
- Instituto de Investigación Hospital Doce de Octubre (imas12), Avenida de Córdoba s/n, 28041 Madrid, Spain.
| | - Víctor G Almendro-Vedia
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
- Instituto de Investigación Hospital Doce de Octubre (imas12), Avenida de Córdoba s/n, 28041 Madrid, Spain.
| | - Elena Junquera
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
| | - José Osío Barcina
- Departamento Química Orgánica, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
| | - Irene Ferrer
- Instituto de Investigación Hospital Doce de Octubre (imas12), Avenida de Córdoba s/n, 28041 Madrid, Spain.
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- Ciberonc, Madrid, Spain
| | - Andrés Guerrero-Martínez
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
| | - Luis Paz-Ares
- Instituto de Investigación Hospital Doce de Octubre (imas12), Avenida de Córdoba s/n, 28041 Madrid, Spain.
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- Ciberonc, Madrid, Spain
- Departamento de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
| | - Iván López-Montero
- Departamento Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain.
- Instituto de Investigación Hospital Doce de Octubre (imas12), Avenida de Córdoba s/n, 28041 Madrid, Spain.
- Instituto Pluridisciplinar, Ps. Juan XXIII 1, 28040 Madrid, Spain
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Blangé D, Stroes CI, Derks S, Bijlsma MF, van Laarhoven HW. Resistance Mechanisms to HER2-Targeted Therapy in Gastroesophageal Adenocarcinoma: A Systematic Review. Cancer Treat Rev 2022; 108:102418. [DOI: 10.1016/j.ctrv.2022.102418] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 12/16/2022]
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Laterza MM, Ciaramella V, Facchini BA, Franzese E, Liguori C, De Falco S, Coppola P, Pompella L, Tirino G, Berretta M, Montella L, Facchini G, Ciardiello F, de Vita F. Enhanced Antitumor Effect of Trastuzumab and Duligotuzumab or Ipatasertib Combination in HER-2 Positive Gastric Cancer Cells. Cancers (Basel) 2021; 13:cancers13102339. [PMID: 34066144 PMCID: PMC8150287 DOI: 10.3390/cancers13102339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary The ToGA trial has demonstrated, in HER2-expressing patients, that unresectable and advanced gastric cancer, chemotherapy and trastuzumab in combination increase overall survival, even if it is still unclear why after one year the same patients are non-responsive to trastuzumab treatment. Here, we have demonstrated that in HER2-positive gastric cancer cell lines, the addition of duligotuzumab, targeting HER3 receptor, or ipatasertib, targeting AKT protein, enhances the antitumor effect of trastuzumab in vitro through a full inhibition of the membrane signals, on HER2 and HER3, and of downstream signaling, including AKT, and MAPK pathways. Hence, this study suggests a novel and biomarker-driven therapeutic strategy supporting further evaluation of the anti-tumor efficacy of these combinations in HER2 human gastric cancer patients. Abstract The anti-HER2 monoclonal antibody trastuzumab is a key drug for the treatment of HER2-positive gastric cancer (GC); however, its activity is often limited by the onset of resistance and mechanisms of resistance are still poorly understood. Several targeted agents showed synergistic activity by concomitant use with trastuzumab in vitro and are under clinical investigation. The aim of this study was to assess the antitumor activity of duligotuzumab, an anti HER3/EGFR antibody or ipatasertib, an AKT inhibitor, combined with trastuzumab in a panel of HER2-positive human gastric cancer cells (GCC), and the efficacy of such combinations in HER2-resistant cells. We have assessed the efficacy of duligotuzumab or ipatasertib and trastuzumab in combination, analyzing proliferation, migration and apoptosis and downstream intracellular signaling in vitro on human HER2-positive GCC (NCI-N87, OE33, OE19) and in negative HER2 GCC (MKN28). We observed a reduction of proliferation, migration and apoptotic rate in HER2-positive OE33, OE19 and N87 cell lines with the combination of duligotuzumab or ipatasertib plus trastuzumab. In particular, in OE33 and OE19 cell lines, the same combined treatment inhibited the activation of proteins downstream of HER2, HER3, AKT and MAPK pathways. Targeting both HER2 and HER3, or HER2 and AKT, results in an improved antitumor effect on HER2-positive GCC.
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Affiliation(s)
- Maria Maddalena Laterza
- UOC Oncologia, ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli-Ischia, 80078 Napoli, Italy; (E.F.); (C.L.); (S.D.F.); (P.C.); (L.M.); (G.F.)
- Correspondence:
| | - Vincenza Ciaramella
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Napoli, Italy; (V.C.); (B.A.F.); (L.P.); (G.T.); (F.C.); (F.d.V.)
| | - Bianca Arianna Facchini
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Napoli, Italy; (V.C.); (B.A.F.); (L.P.); (G.T.); (F.C.); (F.d.V.)
| | - Elisena Franzese
- UOC Oncologia, ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli-Ischia, 80078 Napoli, Italy; (E.F.); (C.L.); (S.D.F.); (P.C.); (L.M.); (G.F.)
| | - Carmela Liguori
- UOC Oncologia, ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli-Ischia, 80078 Napoli, Italy; (E.F.); (C.L.); (S.D.F.); (P.C.); (L.M.); (G.F.)
| | - Stefano De Falco
- UOC Oncologia, ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli-Ischia, 80078 Napoli, Italy; (E.F.); (C.L.); (S.D.F.); (P.C.); (L.M.); (G.F.)
| | - Paola Coppola
- UOC Oncologia, ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli-Ischia, 80078 Napoli, Italy; (E.F.); (C.L.); (S.D.F.); (P.C.); (L.M.); (G.F.)
| | - Luca Pompella
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Napoli, Italy; (V.C.); (B.A.F.); (L.P.); (G.T.); (F.C.); (F.d.V.)
| | - Giuseppe Tirino
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Napoli, Italy; (V.C.); (B.A.F.); (L.P.); (G.T.); (F.C.); (F.d.V.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Liliana Montella
- UOC Oncologia, ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli-Ischia, 80078 Napoli, Italy; (E.F.); (C.L.); (S.D.F.); (P.C.); (L.M.); (G.F.)
| | - Gaetano Facchini
- UOC Oncologia, ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli-Ischia, 80078 Napoli, Italy; (E.F.); (C.L.); (S.D.F.); (P.C.); (L.M.); (G.F.)
| | - Fortunato Ciardiello
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Napoli, Italy; (V.C.); (B.A.F.); (L.P.); (G.T.); (F.C.); (F.d.V.)
| | - Ferdinando de Vita
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Napoli, Italy; (V.C.); (B.A.F.); (L.P.); (G.T.); (F.C.); (F.d.V.)
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Kohli P, Penumadu P, Srinivas BH, M S, Dubashi B, Kate V, Kumar H, R K, Balasubramanian A. Clinicopathological profile and its association with peritoneal disease among gastric cancer patients. Surg Oncol 2021; 38:101595. [PMID: 33991942 DOI: 10.1016/j.suronc.2021.101595] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 03/30/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND There are no clinicopathological criteria or test to predict peritoneal metastasis either in primary or recurrent gastric cancer. The early prediction will help in altering or adding other adjuvant potential therapy modalities like HIPEC and maintenance chemotherapy. METHODS Paraffin based blocks of 110 gastric tumor specimens were subjected to IHC staining to assess VEGF, Her 2 neu, E cadherin, bcl 2 and p 53 expression and its association with peritoneal disease evaluated. RESULTS Her 2 neu uptake was present in 17.3%, bcl-2 expression in 19.1%, P53 expression in 40.9%, VEGF in 41.8% and E cadherin expression in 49.1% patients. On univariate analysis, a younger age(p = .029), female sex(p = .026), positive VEGF expression (p = .001) and p53 expression(p = .015) were significantly associated with peritoneal disease. A binomial logistic regression was performed to ascertain the effects of independent variables evaluated on univariate analysis. Of the 10 predictors variables, only three were statistically significant: tumor type, P53, and VEGF. Positive VEGF expression had 48.7, E cadherin 2.6 and Her2neu 1.5 times higher odds of exhibiting peritoneal disease. CONCLUSION A younger age, female sex, distal 2/3rd, diffuse variant, VEGF staining in >10% cells and decrease p53 expression were associated with peritoneal disease.
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Affiliation(s)
- Pavneet Kohli
- Department of Surgical Oncology, JIPMER, Puducherry, 6050006, India
| | - Prasanth Penumadu
- Department of Surgical Oncology, JIPMER, Puducherry, 6050006, India.
| | - B H Srinivas
- Department of Pathology, JIPMER, Puducherry, 605006, India
| | - Sivasanker M
- HPB Unit, Department of Surgery, Royal Liverpool University Hospitals NHS Trust, Merseyside, UK
| | - Biswajit Dubashi
- Department of Medical Oncology, JIPMER, Puducherry, 605006, India
| | - Vikram Kate
- Department of General Surgery, JIPMER, Puducherry, 605006, India
| | | | - Kalayarasan R
- Department of Surgical Gastroenterology, JIPMER, Puducherry, 605006, India
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Angerilli V, Galuppini F, Businello G, Dal Santo L, Savarino E, Realdon S, Guzzardo V, Nicolè L, Lazzarin V, Lonardi S, Loupakis F, Fassan M. MicroRNAs as Predictive Biomarkers of Resistance to Targeted Therapies in Gastrointestinal Tumors. Biomedicines 2021; 9:biomedicines9030318. [PMID: 33801049 PMCID: PMC8003870 DOI: 10.3390/biomedicines9030318] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
The advent of precision therapies against specific gene alterations characterizing different neoplasms is revolutionizing the oncology field, opening novel treatment scenarios. However, the onset of resistance mechanisms put in place by the tumor is increasingly emerging, making the use of these drugs ineffective over time. Therefore, the search for indicators that can monitor the development of resistance mechanisms and above all ways to overcome it, is increasingly important. In this scenario, microRNAs are ideal candidate biomarkers, being crucial post-transcriptional regulators of gene expression with a well-known role in mediating mechanisms of drug resistance. Moreover, as microRNAs are stable molecules, easily detectable in tissues and biofluids, they are the ideal candidate biomarker to identify patients with primary resistance to a specific targeted therapy and those who have developed acquired resistance. The aim of this review is to summarize the major studies that have investigated the role of microRNAs as mediators of resistance to targeted therapies currently in use in gastro-intestinal neoplasms, namely anti-EGFR, anti-HER2 and anti-VEGF antibodies, small-molecule tyrosine kinase inhibitors and immune checkpoint inhibitors. For every microRNA and microRNA signature analyzed, the putative mechanisms underlying drug resistance were outlined and the potential to be translated in clinical practice was evaluated.
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Affiliation(s)
- Valentina Angerilli
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Francesca Galuppini
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Gianluca Businello
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Luca Dal Santo
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35100 Padua, Italy;
| | - Stefano Realdon
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
| | - Vincenza Guzzardo
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Lorenzo Nicolè
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Vanni Lazzarin
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Sara Lonardi
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
| | - Fotios Loupakis
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
| | - Matteo Fassan
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
- Correspondence: ; Tel.: +39-049-821-1312
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9
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Gouda G, Gupta MK, Donde R, Behera L, Vadde R. Monoclonal Antibody Therapy Against Gastrointestinal Tract Cancers. IMMUNOTHERAPY FOR GASTROINTESTINAL MALIGNANCIES 2020:97-111. [DOI: 10.1007/978-981-15-6487-1_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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10
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Arienti C, Pignatta S, Tesei A. Epidermal Growth Factor Receptor Family and its Role in Gastric Cancer. Front Oncol 2019; 9:1308. [PMID: 31850207 PMCID: PMC6901979 DOI: 10.3389/fonc.2019.01308] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/11/2019] [Indexed: 12/24/2022] Open
Abstract
Despite the gradual decrease in incidence, gastric cancer is still the third leading cause of cancer death worldwide. Although chemotherapy enhances overall survival and quality of life in advanced disease, the median overall survival is < 12 months. In recent years, the human epidermal growth factor receptor (ErbB) family has been extensively investigated in gastric cancer. The ErbB family is composed of four closely-related members: ErbB-1 (HER1 or epidermal growth factor receptor, EGFR), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4), all of which play a critical role in regulating cell growth, proliferation and migration of tumors. It is well known that gastric cancer overexpresses HER in a heterogeneous pattern, especially EGFR, and HER2. HER3 is another important member of the ErbB family that preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway. Furthermore, its heterodimerization with HER2 seems fundamental for steering HER2-overexpressing breast cancer tumor growth. Less is known about the impact of HER4 on gastric cancer. Improved survival from the use of trastuzumab has paved the way for ErbB receptor family-targeted treatments in gastric cancer. However, unlike trastuzumab, ErbB receptor-targeted drugs have not consistently maintained the encouraging results obtained in preclinical and early clinical trials. This may be attributable to the intrinsic heterogeneity of gastric cancer and/or to the lack of standardized test quality for established biomarkers used to evaluate these biological targets. This review presents an overview of the most recent clinical studies on agents targeting the ErbB family in gastric cancer.
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Affiliation(s)
| | | | - Anna Tesei
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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11
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Tirino G, Pompella L, Petrillo A, Laterza MM, Pappalardo A, Caterino M, Orditura M, Ciardiello F, Galizia G, De Vita F. What's New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives. Int J Mol Sci 2018; 19:E2659. [PMID: 30205505 PMCID: PMC6165492 DOI: 10.3390/ijms19092659] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 09/03/2018] [Accepted: 09/05/2018] [Indexed: 02/05/2023] Open
Abstract
Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called "precision medicine" even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions.
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Affiliation(s)
- Giuseppe Tirino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Luca Pompella
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Angelica Petrillo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Maria Maddalena Laterza
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Annalisa Pappalardo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Marianna Caterino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Michele Orditura
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Gennaro Galizia
- Division of GI Tract Surgical Oncology, Department of Cardio-Thoracic and Respiratory Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
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12
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Abstract
Despite major breakthroughs in the field of personalized medicine, gastric cancer (GC) remains a clinically challenging disease, characterized by scarce effective treatment options and the lack of reliable molecular tools for the prediction of patient outcome and response to therapy. The pronounced molecular heterogeneity that dictates the phenotypical aggressiveness of gastric neoplasms severely limits the antitumor efficacy of targeted agents brought to clinical trials, and constitutes a favorable setting for the emergence of refractory tumors exhibiting multidrug resistance. We will review the most recent advances in our understanding of GC biology, which are underlying the development and clinical testing of novel targeted therapeutic agents. We will also emphasize how their efficacy and acquired resistance relate to the aberrant molecular signatures that drive gastric malignancy.
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Affiliation(s)
- Henrique O Duarte
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Joana Gomes
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - José C Machado
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Celso A Reis
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
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13
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Raimondi A, Nichetti F, Peverelli G, Di Bartolomeo M, De Braud F, Pietrantonio F. Genomic markers of resistance to targeted treatments in gastric cancer: potential new treatment strategies. Pharmacogenomics 2018; 19:1047-1068. [PMID: 30041572 DOI: 10.2217/pgs-2018-0077] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is a highly heterogeneous disease, displaying a complex genomic landscape and an unfavorable outcome with standard therapies. Based on distinctive genomic alterations, novel targeted agents have been developed with the aim of personalizing treatments and improving patient outcome. However, a subgroup of patients is primarily treatment-resistant, and even in the initially sensitive population, secondary resistance emerges, thus limiting therapeutic benefit. In this review, we summarize the clinical data about standard targeted agents in gastric cancer, specifically anti-HER2 treatments and antivascular therapies. We also illustrate the available evidence regarding molecular mechanisms of resistance to these agents and we discuss potential strategies for new targeted treatments that could overcome such resistance.
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Affiliation(s)
- Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federico Nichetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giorgia Peverelli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo De Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Oncology & Hemato-oncology, University of Milan, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Oncology & Hemato-oncology, University of Milan, Italy
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14
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Zhu W, Ma L, Qian J, Xu J, Xu T, Pang L, Zhou H, Shu Y, Zhou J. The molecular mechanism and clinical significance of LDHA in HER2-mediated progression of gastric cancer. Am J Transl Res 2018; 10:2055-2067. [PMID: 30093943 PMCID: PMC6079134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 06/08/2018] [Indexed: 06/08/2023]
Abstract
OBJECTIVE The use of human epidermal growth factor receptor-2 (HER2) as a biomarker for gastric cancer (GC) has greatly helped some patients receive benefit from HER2-targeted therapy. However, the correlation between HER2 and other biochemical markers is unclear. The aim of this study was to examine the relationship between HER2 and lactate dehydrogenase A (LDHA) in GC tissues and GC cells. METHODS The correlation between clinicopathological features and HER2 was analyzed in 179 cases of GC. The expression of HER2 and LDHA was examined by immunohistochemical staining in 12 pairs of GC tissues and by western blotting in seven pairs of fresh GC tissues and adjacent normal tissues. Wound healing, transwell migration assay, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR), and LDH activity assays were performed with GC cells. RESULTS HER2 expression and serum LDH levels were closely correlated (P = 0.027) in 179 GC patient cases. Immunohistochemical staining demonstrated a positive correlation between HER2 and LDHA in 12 pairs of GC tissues (P = 0.0308). Knocking down LDHA suppressed cell migration and invasion in GC cells. In addition, HER2 positively regulated hypoxia-inducible factor-1α (HIF-1α) and LDHA. Furthermore, the expressions of HER2, HIF-1α, and LDHA were consistent in 5/7 pairs of fresh GC tissues and adjacent normal tissues as well as in GC cell lines. CONCLUSIONS The HER2-HIF-1α-LDHA axis may serve as the basis for new methods and strategies for the treatment of GC.
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Affiliation(s)
- Weiyou Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
- Cancer Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical UniversitySuzhou 215228, People’s Republic of China
| | - Ling Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
| | - Jing Qian
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
| | - Jin Xu
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, Jiangsu Province, People’s Republic of China
| | - Tongpeng Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
| | - Lijun Pang
- Cancer Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical UniversitySuzhou 215228, People’s Republic of China
| | - Hong Zhou
- Cancer Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical UniversitySuzhou 215228, People’s Republic of China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, People’s Republic of China
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, Jiangsu Province, People’s Republic of China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, People’s Republic of China
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15
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Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol 2018; 24:2818-2832. [PMID: 30018477 PMCID: PMC6048430 DOI: 10.3748/wjg.v24.i26.2818] [Citation(s) in RCA: 308] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/19/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most prevalent malignant types in the world and an aggressive disease with a poor 5-year survival. This cancer is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Although the incidence is declining, the outcome of patients with GC remains dismal. Thus, the detection at an early stage utilizing useful screening approaches, selection of an appropriate treatment plan, and effective monitoring is pivotal to reduce GC mortalities. Identification of biomarkers in a basis of clinical information and comprehensive genome analysis could improve diagnosis, prognosis, prediction of recurrence and treatment response. This review summarized the current status and approaches in GC biomarker, which could be potentially used for early diagnosis, accurate prediction of therapeutic approaches and discussed the future perspective based on the molecular classification and profiling.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masakazu Yashiro
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
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16
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Kubota T, Kuroda S, Kanaya N, Morihiro T, Aoyama K, Kakiuchi Y, Kikuchi S, Nishizaki M, Kagawa S, Tazawa H, Fujiwara T. HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 14:1919-1929. [PMID: 29885899 DOI: 10.1016/j.nano.2018.05.019] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 05/07/2018] [Accepted: 05/29/2018] [Indexed: 01/17/2023]
Abstract
An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.
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Affiliation(s)
- Tetsushi Kubota
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinji Kuroda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan.
| | - Nobuhiko Kanaya
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Toshiaki Morihiro
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Katsuyuki Aoyama
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshihiko Kakiuchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoru Kikuchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan
| | - Masahiko Nishizaki
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan
| | - Hiroshi Tazawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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17
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Chuang YC, Wu HY, Lin YL, Tzou SC, Chuang CH, Jian TY, Chen PR, Chang YC, Lin CH, Huang TH, Wang CC, Chan YL, Liao KW. Blockade of ITGA2 Induces Apoptosis and Inhibits Cell Migration in Gastric Cancer. Biol Proced Online 2018; 20:10. [PMID: 29743821 PMCID: PMC5928594 DOI: 10.1186/s12575-018-0073-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/28/2018] [Indexed: 12/19/2022] Open
Abstract
Background Gastric cancer is currently the fourth leading cause of cancer-related death worldwide. Gastric cancer is often diagnosed at advanced stages and the outcome of the treatment is often poor. Therefore, identifying new therapeutic targets for this cancer is urgently needed. Integrin alpha 2 (ITGA2) subunit and the beta 1 subunit form a heterodimer for a transmembrane receptor for extracellular matrix, is an important molecule involved in tumor cell proliferation, survival and migration. Integrin α2β1 is over-expressed on a variety of cancer cells, but is low or absent in most normal organs and resting endothelial cells. Results In this report, we assessed the ITGA2 as the potential therapeutic target with the bioinformatics tools from the TCGA dataset in which composed of 375 gastric cancer tissues and 32 gastric normal tissues. According to the information from the Cancer Cell Line Encyclopedia (CCLE) database, the AGS cell line with ITGA2 high expression and the SUN-1 cell line with low expression were chosen for the further investigation. Interestingly, the anti-ITGA2 antibody (at 3 μg/ml) inhibited approximately 50% survival of the AGS cells (over-expressed ITGA2), but had no effect in SNU-1 cells (ITGA2 negative). The extents of antibody-mediated cancer inhibition positively correlated with the expression levels of the ITGA2. We further showed that the anti-ITGA2 antibody induced apoptosis by up-regulating the RhoA-p38 MAPK signaling to promote the expressions of Bim, Apaf-1 and Caspase-9, whereas the expressions of Ras and Bax/Bcl-2 were not affected. Moreover, blocking ITGA2 by the specific antibody at lower doses also inhibited cell migration of gastric cancer cells. Blockade of ITGA2 by a specific antibody down-regulated the expression of N-WASP, PAK and LIMK to impede actin organization and cell migration of gastric cancer cells. Conclusions Here, we showed that the mRNA expression levels of ITGA2 comparing to normal tissues significantly increased. In addition, the results revealed that targeting integrin alpha 2 subunit by antibodies did not only inhibit cell migration, but also induce apoptosis effect on gastric cancer cells. Interestingly, higher expression level of ITGA2 led to significant effects on apoptosis progression during anti-ITGA2 antibody treatment, which indicated that ITGA2 expression levels directly correlate with their functionality. Our findings suggest that ITGA2 is a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Yu-Chang Chuang
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Hsin-Yi Wu
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Yu-Ling Lin
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,3Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, Taiwan, Republic of China
| | - Shey-Cherng Tzou
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Cheng-Hsun Chuang
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Ting-Yan Jian
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Pin-Rong Chen
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Yuan-Ching Chang
- 4Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Chi-Hsin Lin
- 5Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Tse-Hung Huang
- 6Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China.,7School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.,8School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, Republic of China
| | - Chao-Ching Wang
- 6Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
| | - Yi-Lin Chan
- 9Department of Life Science, Chinese Culture University, 55, Hwa-Kang Rd., Yang-Ming-Shan, Taipei, 11114 Taiwan, Republic of China
| | - Kuang-Wen Liao
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,10College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, Republic of China.,11Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.,12Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China
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18
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Liu D, Li X, Chen C, Li C, Zhou C, Zhang W, Zhao J, Fan J, Cheng K, Chen L. Target-specific delivery of oxaliplatin to HER2-positive gastric cancer cells in vivo using oxaliplatin-au-fe3o4-herceptin nanoparticles. Oncol Lett 2018; 15:8079-8087. [PMID: 29731915 DOI: 10.3892/ol.2018.8323] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 12/14/2017] [Indexed: 01/14/2023] Open
Abstract
Gastric cancer is the fourth most common malignancy globally. In order to decrease the dosage and side effects of conventional chemotherapy, and achieve improved benefits from molecular targeted therapy, novel drug delivery systems were developed in the present study. Oxaliplatin-Au-Fe3O4-Herceptin® acts as a dual-functional nanoparticles (NPs) conjugate and possesses the capability of human epithelial growth factor receptor 2 (HER2) targeting and oxaliplatin delivery. The 8-20 nm Au-Fe3O4 were synthesized by decomposing iron pentacarbonyl on the surfaces of Au NPs in the presence of oleic acid and oleylamine. Following being coated with polyethylene glycol, the NPs possessed a ζ-potential of 13.8±1.6 mV and were demonstrated to exhibit no cytotoxicity when Fe concentration is <100 µg/ml via an MTS assay. Mass spectrometry analysis detected a peak at m/z 148,000, and Nuclear Magnetic Resonance indicated peaks at δ 3.51 (8.00H, s, 3-H), 2.97-3.02 (3.80H, t, 2-H) and 2.72-2.76 (3.72H, t, 1-H) following successful loading with Herceptin and oxaliplatin probes. A drug release assay via dialysis cassettes demonstrated that 25% of the oxaliplatin was released at pH 8.0, however >58% was released at pH 6.0 following 4 h incubation, indicating its pH-dependent release characteristic. The active targeting feature of oxaliplatin-Au-Fe3O4-Herceptin was verified in a subcutaneous xenograft mouse model containing SGC-7901 cells via detecting aggregated low intensity in T2-weighted magnetic resonance imaging, which was further confirmed by immunohistochemistry. Therefore, oxaliplatin-Au-Fe3O4-Herceptin is a promising multifunctional platform for simultaneous magnetic traceable and HER2 targeted chemotherapy for gastric cancer.
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Affiliation(s)
- Daren Liu
- Department of General Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Xiaowen Li
- Department of General Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Changlei Chen
- Key Laboratory of Applied Chemistry of Zhejiang, Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Chao Li
- Department of General Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Chuanbiao Zhou
- Department of General Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Weidong Zhang
- Department of General Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Jiangang Zhao
- Department of General Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Jie Fan
- Key Laboratory of Applied Chemistry of Zhejiang, Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Kai Cheng
- Molecular Imaging Program, Canary Center for Cancer Early Detection, Department of Radiology and Bio-X Program, Stanford University, Stanford, CA 94305, USA
| | - Li Chen
- Department of General Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
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19
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Yun S, Koh J, Nam SK, Park JO, Lee SM, Lee K, Lee KS, Ahn SH, Park DJ, Kim HH, Choe G, Kim WH, Lee HS. Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients. Gastric Cancer 2018; 21:225-236. [PMID: 28573357 DOI: 10.1007/s10120-017-0732-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 05/25/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Neuregulin 1 (NRG1), a ligand for human epidermal growth factor (HER) 3 and HER4, can activates cell signaling pathways to promote carcinogenesis and metastasis. METHODS To investigate the clinicopathologic significance of NRG1 and its receptors, immunohistochemistry was performed for NRG1, HER3, and HER4 in 502 consecutive gastric cancers (GCs). Furthermore, HER2, microsatellite instability (MSI), and Epstein-Barr virus (EBV) status were investigated. NRG1 gene copy number (GCN) was determined by dual-color fluorescence in situ hybridization (FISH) in 388 available GCs. RESULTS NRG1 overexpression was observed in 141 (28.1%) GCs and closely correlated with HER3 (P = 0.034) and HER4 (P < 0.001) expression. NRG1 overexpression was significantly associated with aggressive features, including infiltrative tumor growth, lymphovascular, and neural invasion, high pathologic stage, and poor prognosis (all P < 0.05), but not associated with EBV, MSI, or HER2 status. Multivariate analysis identified NRG1 overexpression as an independent prognostic factor for survival (P = 0.040). HER3 and HER4 expressions were observed in 157 (31.3%) and 277 (55.2%), respectively. In contrast to NRG1, expression of these proteins was not associated with survival. NRG1 GCN gain (GCN ≥ 2.5) was detected in 14.7% patients, including two cases of amplification, and was moderately correlated with NRG1 overexpression (κ, 0.459; P < 0.001). CONCLUSIONS Although our results indicate a lack of prognostic significance of HER3 and HER4 overexpression in GC, overexpression of their ligand, NRG1, was associated with aggressive clinical features and represented an independent unfavorable prognostic factor. Therefore, NRG1 is a potential prognostic and therapeutic biomarker in GC patients.
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Affiliation(s)
- Sumi Yun
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.,Department of Diagnostic Pathology, Samkwang Medical Laboratories, Seoul, South Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Jung Ok Park
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Sung Mi Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Kyoungyul Lee
- Department of Pathology, Kangwon National University Hospital, Chuncheon, Kangwon, South Korea
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Gheeyoung Choe
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea.
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20
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Zhou X, Men X, Zhao R, Han J, Fan Z, Wang Y, Lv Y, Zuo J, Zhao L, Sang M, Liu XD, Shan B. miR-200c inhibits TGF-β-induced-EMT to restore trastuzumab sensitivity by targeting ZEB1 and ZEB2 in gastric cancer. Cancer Gene Ther 2018; 25:68-76. [DOI: 10.1038/s41417-017-0005-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/12/2017] [Accepted: 10/20/2017] [Indexed: 02/08/2023]
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21
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Arienti C, Pignatta S, Zanoni M, Cortesi M, Zamagni A, Piccinini F, Tesei A. Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down. J Vis Exp 2017. [PMID: 29286488 DOI: 10.3791/56583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The past two decades have seen a shift from cytotoxic drugs to targeted therapy in medical oncology. Although targeted therapeutic agents have shown more impressive clinical efficacy and minimized adverse effects than traditional treatments, drug resistance has become the main limitation to their benefits. Several preclinical in vitro/in vivo models of acquired resistance to targeted agents in clinical practice have been developed mainly by using two strategies: i) genetic manipulation for modeling genotypes of acquired resistance, and ii) in vitro/in vivo selection of resistant models. In the present work, we propose a unifying framework, for investigating the underlying mechanisms responsible for acquired resistance to targeted therapeutic agents, starting from the generation of drug-resistant cellular subclones to the description of silencing procedures used for restoring the sensitivity to the inhibitor. This simple time- and cost-effective approach is widely applicable, and could be easily extended to investigate resistance mechanisms to other targeted therapeutic drugs in different tumor histotypes.
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Affiliation(s)
- Chiara Arienti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
| | - Sara Pignatta
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
| | - Michele Zanoni
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
| | - Michela Cortesi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
| | - Alice Zamagni
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
| | - Filippo Piccinini
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
| | - Anna Tesei
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS;
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22
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Li L, Li Y, Wang L, Wu Z, Ma H, Shao J, Li D, Yu H, Nian W, Wang D. Inhibition of Hes1 enhances lapatinib sensitivity in gastric cancer sphere-forming cells. Oncol Lett 2017; 14:3989-3996. [PMID: 28959362 PMCID: PMC5607651 DOI: 10.3892/ol.2017.6683] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 05/26/2017] [Indexed: 01/26/2023] Open
Abstract
It has been considered that the neurogenic locus notch homolog protein (Notch) signaling pathway serves an essential role in cellular differentiation, proliferation and apoptosis. However, the function of the Notch signaling pathway in gastric cancer stem cells (GCSCs) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sensitivity remains unclear. The present study aimed to delineate the role of the Notch1 signaling pathway in GCSCs and lapatinib sensitivity. Sphere-forming cells were separated from human gastric cancer MKN45 parental cells. The sphere-forming cells exhibited characteristics of CSCs and higher Notch1 expression compared with that of parental cells. To investigate the role of the Notch1 signaling pathway in GCSCs, the expression of transcription factor Hes1 (Hes1) was knocked down using small interfering RNA against Hes1. It was observed that Hes1 expression was significantly downregulated in knocked down cells. The inhibition of Hes1 suppressed the properties of CSCs, as indicated by significant decreases in the expression of the transcription factor sex determining region Y-box 2, epithelial cell adhesion molecule and the homeobox protein Nanog and reduced spheroid colony formation. In addition, epithelial-mesenchymal transition was significantly impaired in sphere-forming cells following Hes1 knockdown. Furthermore, the inhibition of Hes1 effectively enhanced lapatinib sensitivity in sphere-forming cells. These results suggest that sphere-forming gastric cancer cells possess the characteristics of CSCs, and that the Notch1 signaling pathway serves an essential role in the maintenance of CSCs and lapatinib sensitivity.
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Affiliation(s)
- Luchun Li
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Yan Li
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Lulu Wang
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Zhijuan Wu
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Huiwen Ma
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Jianghe Shao
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Dairong Li
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Huiqing Yu
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Weiqi Nian
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Donglin Wang
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
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23
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Garattini SK, Basile D, Cattaneo M, Fanotto V, Ongaro E, Bonotto M, Negri FV, Berenato R, Ermacora P, Cardellino GG, Giovannoni M, Pella N, Scartozzi M, Antonuzzo L, Silvestris N, Fasola G, Aprile G. Molecular classifications of gastric cancers: Novel insights and possible future applications. World J Gastrointest Oncol 2017; 9:194-208. [PMID: 28567184 PMCID: PMC5434387 DOI: 10.4251/wjgo.v9.i5.194] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/04/2016] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Despite some notable advances in the systemic management of gastric cancer (GC), the prognosis of patients with advanced disease remains overall poor and their chance of cure is anecdotic. In a molecularly selected population, a median overall survival of 13.8 mo has been reached with the use of human epidermal growth factor 2 (HER2) inhibitors in combination with chemotherapy, which has soon after become the standard of care for patients with HER2-overexpressing GC. Moreover, oncologists have recognized the clinical utility of conceiving cancers as a collection of different molecularly-driven entities rather than a single disease. Several molecular drivers have been identified as having crucial roles in other tumors and new molecular classifications have been recently proposed for gastric cancer as well. Not only these classifications allow the identification of different tumor subtypes with unique features, but also they serve as springboard for the development of different therapeutic strategies. Hopefully, the application of standard systemic chemotherapy, specific targeted agents, immunotherapy or even surgery in specific cancer subgroups will help maximizing treatment outcomes and will avoid treating patients with minimal chance to respond, therefore diluting the average benefit. In this review, we aim at elucidating the aspects of GC molecular subtypes, and the possible future applications of such molecular analyses.
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24
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Ebbing EA, Medema JP, Damhofer H, Meijer SL, Krishnadath KK, van Berge Henegouwen MI, Bijlsma MF, van Laarhoven HWM. ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3. Oncotarget 2016; 7:10243-54. [PMID: 26863569 PMCID: PMC4891117 DOI: 10.18632/oncotarget.7200] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 01/23/2016] [Indexed: 01/24/2023] Open
Abstract
Receptor tyrosine kinases of the HER-family are involved in the development and progression of multiple epithelial tumors, and have consequently become widely used targets for new anti-cancer therapies. Trastuzumab, an antibody against HER2, has shown potent growth inhibitory effects on HER2 overexpressing tumors, including gastro-esophageal cancer, however, resistance to this therapy is inevitable. Unfortunately, a paucity of data on the cellular mechanisms of resistance to targeted therapeutic agents exists in esophageal adenocarcinoma. Using primary established HER2-overexpressing cultures and patient-derived xenograft models, we now reveal a novel resistance mechanism to trastuzumab in esophageal cancer: In response to trastuzumab, both HER3 and the metalloprotease ADAM10 are simultaneously upregulated. The proteolytic activity of the latter then releases the HER3 ligand heregulin from the cell surface to activate HER3 and confer resistance to trastuzumab by inducing compensatory growth factor receptor signaling. Blocking either HER3 or ADAM10 effectively reverts the acquired resistance to trastuzumab. Our data thus provide strategies to inhibit this signaling and circumvent resistance to trastuzumab.
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Affiliation(s)
- Eva A Ebbing
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.,Department of Medical Oncology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.,Cancer Genomics Center, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Helene Damhofer
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Sybren L Meijer
- Department of Pathology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Kausilia K Krishnadath
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.,Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | | | - Maarten F Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
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25
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Kneissl J, Hartmann A, Pfarr N, Erlmeier F, Lorber T, Keller S, Zwingenberger G, Weichert W, Luber B. Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines. J Cancer Res Clin Oncol 2016; 143:573-600. [PMID: 27933395 PMCID: PMC5352771 DOI: 10.1007/s00432-016-2308-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/17/2016] [Indexed: 12/18/2022]
Abstract
Purpose Gastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab. Methods A panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity. Results We found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab. Conclusions Our data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer. Electronic supplementary material The online version of this article (doi:10.1007/s00432-016-2308-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Julia Kneissl
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Anja Hartmann
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Nicole Pfarr
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Franziska Erlmeier
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Thomas Lorber
- Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland
| | - Simone Keller
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Gwen Zwingenberger
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Wilko Weichert
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Birgit Luber
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
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26
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A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells. Apoptosis 2016; 20:1599-612. [PMID: 26437915 DOI: 10.1007/s10495-015-1164-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in cancer therapy, and HER2 protein-tyrosine kinase inhibitors have attracted considerable attention in the field of searching for novel anticancer drug candidates. In this study, we investigated the anticancer effect of KU004, a novel dual EGFR and HER2 inhibitor in vitro and in vivo. In vitro, KU004 preferentially inhibited the growth of HER2-overexpressing breast and gastric cell lines and HER2 expression level significantly correlated with response to KU004. It blocked activation of EGFR, HER2 and downstream Akt and Erk and induced G0/G1 arrest which was associated with downregulation of p53, p21, cyclin D1 and CDK4 along with increase of p27 and dephosphorylation of pRb. Apoptosis occurred in a caspase-dependent manner mainly via the extrinsic apoptotic pathway after KU004 treatment. The in vitro efficacy of KU004 was comparable to that of lapatinib. Moreover, KU004 suppressed the growth of NCI-N87 tumor and induced apoptosis without causing apparent weight loss or obvious toxicity. Tumor volume was significantly smaller in KU004-treated group than that in lapatinib-treated group at comparable dose levels. Taken together, these findings demonstrate KU004 can be expected to be a promising anti-HER2 candidate.
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27
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Thura M, Al-Aidaroos AQO, Yong WP, Kono K, Gupta A, Lin YB, Mimura K, Thiery JP, Goh BC, Tan P, Soo R, Hong CW, Wang L, Lin SJ, Chen E, Rha SY, Chung HC, Li J, Nandi S, Yuen HF, Zhang SD, Guan YK, So J, Zeng Q. PRL3-zumab, a first-in-class humanized antibody for cancer therapy. JCI Insight 2016; 1:e87607. [PMID: 27699276 DOI: 10.1172/jci.insight.87607] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3-, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become "extracellular oncotargets" that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.
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Affiliation(s)
- Min Thura
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | | | - Wei Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Koji Kono
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Division of General Surgery (Upper Gastrointestinal Surgery), National University Hospital, Singapore
| | - Abhishek Gupta
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - You Bin Lin
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Kousaku Mimura
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Jean Paul Thiery
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Boon Cher Goh
- Department of Haematology-Oncology, National University Cancer Institute, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Patrick Tan
- Genome Institute of Singapore, A*STAR, Singapore
| | - Ross Soo
- Department of Haematology-Oncology, National University Cancer Institute, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | - Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | - Elya Chen
- Division of General Surgery (Upper Gastrointestinal Surgery), National University Hospital, Singapore
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei Cancer Research Institute, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyun Cheol Chung
- Department of Internal Medicine, Yonsei Cancer Research Institute, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Jie Li
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Sayantani Nandi
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Hiu Fung Yuen
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Shu-Dong Zhang
- Northern Ireland Centre for Stratified Medicine, Ulster University, C-TRIC, Londonderry, United Kingdom
| | - Yeoh Khay Guan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jimmy So
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Surgical Oncology (Upper Gastrointestinal Surgery), National University Cancer Institute, Singapore
| | - Qi Zeng
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
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28
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Arienti C, Zanoni M, Pignatta S, Del Rio A, Carloni S, Tebaldi M, Tedaldi G, Tesei A. Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer. Oncotarget 2016; 7:18424-39. [PMID: 26919099 PMCID: PMC4951299 DOI: 10.18632/oncotarget.7575] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 02/11/2016] [Indexed: 12/17/2022] Open
Abstract
HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2-signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.
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Affiliation(s)
- Chiara Arienti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Michele Zanoni
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Sara Pignatta
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alberto Del Rio
- Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna, Italy
- Innovamol Srls, Modena, Italy
| | - Silvia Carloni
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Michela Tebaldi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Gianluca Tedaldi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Anna Tesei
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer. Cancer Chemother Pharmacol 2016; 77:957-62. [DOI: 10.1007/s00280-016-3013-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 03/15/2016] [Indexed: 12/27/2022]
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Abstract
Background Gastric cancer is the fourth most common cancer worldwide. Surgery in combination with multimodal therapy provides the only curative therapy until now. The importance of targeted therapy became clear over the last few years. Due to the implication of HER2 and angiogenesis-directed targeted therapies major advances in the treatment of gastric cancer could be reached. Nevertheless, benefits in survival remain unsatisfactory and the development of resistance to monoclonal antibodies is arising. Methods A comprehensive and comparative literature research was performed to evaluate the status of HER2 and angiogenesis-directed targeted therapy in gastric cancer. Results Up to now, trastuzumab and ramucirumab are the only agents showing remarkable benefits in the therapy for the patients suffering from gastric cancer. The limitations of targeted therapies in gastric cancer are mainly associated with the development of secondary resistance. Conclusion Addition of targeted therapy in second-line treatment is beneficial when compared with chemotherapy alone. Nevertheless, results in first-line treatment remain modest. Therefore, new therapeutic agents and combinations in the first-line treatment of gastric cancer are urgently needed and remain to be validated in clinical trials.
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Affiliation(s)
- G Jomrich
- Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC), Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria
| | - S F Schoppmann
- Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC), Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria
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Li H, Yu C, Jiang J, Huang C, Yao X, Xu Q, Yu F, Lou L, Fang J. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther 2016; 17:346-54. [PMID: 26853765 DOI: 10.1080/15384047.2016.1139248] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Antibody-drug conjugate (ADC) is a novel class of therapeutics for cancer target therapy. This study assessed antitumor activity of ADC with an antimitotic agent, monomethyl auristatin E (MMAE) and a humanized monoclonal anti-HER2 antibody, hertuzumab, in gastric cancer. The efficacy of hertuzumab-MC-Val-Cit-PAB-MMAE (hertuzumab-vcMMAE) on human epidermal growth factor receptor 2 (HER2) positive human gastric cancer cells, NCI-N87, was evaluated in vitro and in vivo. The cytotoxicity of hertuzumab was significantly enhanced after conjugation with MMAE. Compared to trastuzumab, hertuzumab had a higher affinity to HER2 and had more potent antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. After conjugation with MMAE, the binding specificity for HER2 was not affected. Furthermore, the internalization of hertuzumab-vcMMAE in HER2 positive gastric cancer cells was verified. Although the conjugation of hertuzumab and MMAE decreased the ADCC effect, the overall cytotoxicity was dramatically increased in HER2 positive gastric cancer cells. In vitro data on this hertuzumab-vcMMAE has exerted much stronger antitumor activity compared to trastuzumab-DM1 in HER2 positive gastric cancer cells. A single administration of hertuzumab-vcMMAE at 5 or 10 mg/kg showed high potency and a sustained tumor inhibitory effect on NCI-N87 xenografts in mice. In conclusion, hertuzumab-vcMMAE conjugate is a highly effective anti-HER2 targeted therapy for HER2-positive gastric cancer.
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Affiliation(s)
- Hongwen Li
- a School of Life Sciences and Technology, Tongji University , Shanghai , China
| | - Chao Yu
- b RemeGen, Ltd. , Yantai , Shandong , China
| | - Jing Jiang
- c School of Pharmacy, Binzhou Medical University , Yantai , Shandong , China
| | | | - Xuejing Yao
- a School of Life Sciences and Technology, Tongji University , Shanghai , China
| | - Qiaoyu Xu
- b RemeGen, Ltd. , Yantai , Shandong , China
| | - Fang Yu
- b RemeGen, Ltd. , Yantai , Shandong , China
| | - Liguang Lou
- d Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
| | - Jianmin Fang
- a School of Life Sciences and Technology, Tongji University , Shanghai , China.,e Tongji University Suzhou Institute , Suzhou , Jiangsu , China.,f Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China
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Lee SY, Oh SC. Changing strategies for target therapy in gastric cancer. World J Gastroenterol 2016; 22:1179-89. [PMID: 26811656 PMCID: PMC4716029 DOI: 10.3748/wjg.v22.i3.1179] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/08/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of targeted therapy. Firstly, many patients with metastatic gastric cancer who receive trastuzumab in combination with chemotherapeutic agents develop resistance to the targeted therapy. Secondly, many clinical trials testing novel molecular targeted agents with demonstrated efficacy in other malignancies have failed to show benefit in patients with metastatic gastric cancer, suggesting the importance of the selection of appropriate indications according to molecular characteristics in application of targeted agents. Herein, we review the molecular targeted agents currently approved and in use, and clinical trials in patients with metastatic gastric cancer, and demonstrate the limitations and future direction in treatment of advanced gastric cancer.
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Abstract
Gastric cancer is one of the most commonly diagnosed and the second leading cause of cancer death worldwide. Surgery combined with multimodal therapy remains the only curative therapy. However, local relapse or distant metastases occur in more than 50% of radically resected patients. Due to molecular therapies, targeting HER2 and angiogenesis, major advances in the treatment of gastric cancer could be achieved. Nevertheless, development of resistance to monoclonal antibodies, such as trastuzumab, is arising. Currently a number of promising new therapeutic are under investigation, combining chemotherapy with newly developed agents to overcome cancer resistance. In this review we report current clinical applications of targeted therapies and overview ongoing trials, investigating the use of monoclonal antibodies in (HER2 positive) gastric cancer.
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Affiliation(s)
- G Jomrich
- a Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC) , Medical University of Vienna , Vienna , Austria
| | - S F Schoppmann
- a Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC) , Medical University of Vienna , Vienna , Austria
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He J, Shi H, Zhou Z, Chen J, Guan W, Wang H, Yu H, Liu S, Zhou Z, Yang X, Liu T. Correlation between apparent diffusion coefficients and HER2 status in gastric cancers: pilot study. BMC Cancer 2015; 15:749. [PMID: 26487555 PMCID: PMC4618135 DOI: 10.1186/s12885-015-1726-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 10/08/2015] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND To evaluate whether apparent diffusion coefficient (ADC) value of gastric cancer obtained from diffusion weighted imaging (DWI) correlates with the HER2 status. METHODS Forty-five patients, who had been diagnosed with gastric cancer through biopsy, were enrolled in this IRB-approved study. Each patient underwent a DWI (b values: 0 and 1,000 sec/mm(2)) prior to surgery (curative gastrectomy or palliative resection). Postoperative microscopic findings, HER2 status by immunohistochemical analysis and fluorescence in situ hybridization (FISH) were obtained. HER2 status was compared among gastric cancers with various histopathological features using the chi square test. The ADC values of gastric cancers with positive and negative HER2 were compared using the student t test. RESULTS A weak yet significant correlation was observed between the mean ADC values and HER2 status (r = 0.312, P = 0.037) and scores (r = 0.419, P = 0.004). The mean ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.211 vs. 0.984 mm(2)/s, P = 0.020). The minimal ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.105 vs. 0.905 × 10(-3) mm(2)/s, P = 0.036). CONCLUSIONS In this pilot study, we have demonstrated that the ADC values of gastric cancer correlate with the HER2 status. Future research is warranted to see if DWI can predict HER2 status and help in tailoring therapy for gastric cancer.
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Affiliation(s)
- Jian He
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Hua Shi
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Zhuping Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Jun Chen
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Wenxian Guan
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Hao Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Haiping Yu
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Song Liu
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Zhengyang Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Xiaofeng Yang
- Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
| | - Tian Liu
- Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
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Leto SM, Sassi F, Catalano I, Torri V, Migliardi G, Zanella ER, Throsby M, Bertotti A, Trusolino L. Sustained Inhibition of HER3 and EGFR Is Necessary to Induce Regression of HER2-Amplified Gastrointestinal Carcinomas. Clin Cancer Res 2015; 21:5519-31. [PMID: 26296355 DOI: 10.1158/1078-0432.ccr-14-3066] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 08/13/2015] [Indexed: 12/21/2022]
Abstract
PURPOSE Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities. EXPERIMENTAL DESIGN The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstream transducers was evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversible HER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays. RESULTS Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was also very effective in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib-or, importantly, monotherapy with afatinib-resulted in overt tumor shrinkage. CONCLUSIONS Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res; 21(24); 5519-31. ©2015 AACR.
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Affiliation(s)
- Simonetta M Leto
- Department of Oncology, University of Turin Medical School, Turin, Italy. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Turin, Italy
| | - Francesco Sassi
- Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Turin, Italy
| | - Irene Catalano
- Department of Oncology, University of Turin Medical School, Turin, Italy. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Turin, Italy
| | - Valter Torri
- Laboratory of Methodology for Biomedical Research, Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Giorgia Migliardi
- Department of Oncology, University of Turin Medical School, Turin, Italy. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Turin, Italy
| | - Eugenia R Zanella
- Department of Oncology, University of Turin Medical School, Turin, Italy. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Turin, Italy
| | | | - Andrea Bertotti
- Department of Oncology, University of Turin Medical School, Turin, Italy. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Turin, Italy. Istituto Nazionale di Biostrutture e Biosistemi, INBB, Rome, Italy.
| | - Livio Trusolino
- Department of Oncology, University of Turin Medical School, Turin, Italy. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Turin, Italy.
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Saito T, Kondo C, Shitara K, Ito Y, Saito N, Ikehara Y, Yatabe Y, Yamamichi K, Tanaka H, Nakanishi H. Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case. Pathol Int 2015; 65:309-17. [PMID: 25828363 DOI: 10.1111/pin.12290] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Accepted: 02/27/2015] [Indexed: 12/17/2022]
Abstract
Intratumoral heterogeneity of HER2 expression in the metastatic foci of HER2-positive advanced gastric cancer remains unclear. In this study, we compared HER2 expression between primary and metastatic tumors in HER2-positive three autopsied cases and one resected case with multiple organ metastases by immunohistochemistry (IHC) and dual color in situ hybridization (DISH). All four cases judged positive (IHC3+) at the primary tumor tissues showed varying HER2 gene amplification (GA) status. One homogeneously HER2-positive autopsied case (Case 1) and one intratumorally heterogeneous positive resected case (Case 2) with high GA showed a homogeneous positive staining pattern in all the metastatic foci. One heterogeneously HER2-positive autopsied case (Case 3) with low GA showed a partially heterogeneous HER2 staining pattern in all the metastatic foci. In contrast, one heterogeneously HER2-positive autopsied case (Case 4) with equivocal GA showed a completely heterogeneous HER2 staining pattern in the metastatic foci. These results indicate that HER2-positive gastric cancers with low to high GA at the primary tumor show substantially homogeneous HER2 overexpression in the metastatic foci, whereas HER2-positive gastric cancers with equivocal GA expressed HER2 heterogeneously within the metastatic tumor, suggesting that metastatic foci of the latter HER2-positive cases would be potentially resistant to trastuzumab.
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Affiliation(s)
- Takuya Saito
- Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chihiro Kondo
- Department of Clinical Oncology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - Yuichi Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Noriko Saito
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Yuzuru Ikehara
- Molecular Medicine Team, Research Centre for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Keigo Yamamichi
- Department of Surgery, Osaka Saiseikai Izuo Hospital, Osaka, Japan
| | - Hideo Tanaka
- Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hayao Nakanishi
- Laboratory of Pathology and Clinical Research, Aichi Cancer Center, Aichi Hospital, Okazaki, Japan
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Dokmanovic M, Wu WJ. Monitoring Trastuzumab Resistance and Cardiotoxicity: A Tale of Personalized Medicine. Adv Clin Chem 2015; 70:95-130. [PMID: 26231486 DOI: 10.1016/bs.acc.2015.03.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
While approval of trastuzumab, a recombinant monoclonal antibody directed against HER2, along with a diagnostic kit to detect breast cancers which are positive for HER2 overexpression, has advanced a new era of stratified and personalized medicine, it also created several challenges to our scientific and clinical practice. These problems include trastuzumab resistance and trastuzumab-induced cardiotoxicity. In this review, we will summarize data from the literature regarding mechanisms of trastuzumab resistance and trastuzumab-induced cardiotoxicity and present some promising model systems that may advance our understanding of these mechanisms. Our discussion will include development of circulating tumor cells and circulating tumor DNA for monitoring tumor burden, of patient-derived xenograft models for preclinical testing of novel therapies, and of novel therapeutic strategies for trastuzumab-resistance and possible integration of these strategies in the design of co-clinical studies for testing in relevant patient subpopulations.
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Wang L, Yuan H, Li Y, Han Y. The role of HER3 in gastric cancer. Biomed Pharmacother 2014; 68:809-12. [PMID: 25194439 DOI: 10.1016/j.biopha.2014.08.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 08/06/2014] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer is the second leading cause of cancer mortality in the world. HER family tyrosine kinases play a critical role in the development of gastric cancer. The HER family of receptor tyrosine kinases includes EGF receptor (EGFR), HER2, HER3, and HER4. Targeted drugs antineoplastic therapies such as EGFR tyrosine kinase inhibitors have application with confrontation of gastric cancer. However, less attention has been paid to the oncogenic functions of HER3 essepecially in the gastric cancer due to its lack of intrinsic kinase activity. Recent work, however, has placed the role of HER3 in gastric cancer in the spotlight as a key signaling hub in several contexts. First, HER3 overexpression may be associated with poor prognosis and unfavorable survival mediated by PI3K/AKT signaling pathway. Second, a large amount of direct evidence has emerged the benefit of anti-HER3 agents in combination with EGFR tyrosine kinase inhibitors as well as anti-HER2 agents in gastric cancer. Furthermore, we can further elucidate the relationship between HER3 and MET inhibitors in gastric cancer that the development of resistance to MET inhibitors may result from the overexpression of HER3. This review focuses on the current achievements of the relationship between HER3 and gastric cancer in vivo and in vitro, the development of HER3 molecule-targeted therapy, additionally, the challenge which we will meet in the future.
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Affiliation(s)
- Liying Wang
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, Harbin, PR China
| | - Hengheng Yuan
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, Harbin, PR China
| | - Yanjing Li
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, Harbin, PR China
| | - Yu Han
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, Harbin, PR China.
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