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Desai O, Rathore M, Boutros CS, Wright M, Bryson E, Curry K, Wang R. HER3: Unmasking a twist in the tale of a previously unsuccessful therapeutic pursuit targeting a key cancer survival pathway. Genes Dis 2025; 12:101354. [PMID: 40290122 PMCID: PMC12022662 DOI: 10.1016/j.gendis.2024.101354] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 04/30/2025] Open
Abstract
HER3, formally referred to as ERB-B2 receptor tyrosine kinase 3, is a member of the ErbB receptor tyrosine kinases (also known as EGFR) family. HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation, which initiates downstream signaling pathways crucial in cancer cell survival and progression. As a result, numerous monoclonal antibodies have been developed to block HER3 activation and subsequent signaling pathways. While pre-clinical investigations have effectively showcased significant anti-cancer effects of HER3-targeted therapies, these therapies have had little impact on cancer patient outcomes in the clinic, except for patients with rare NRG1 fusion mutations. This review offers a comprehensive description of the oncogenic functions of HER3, encompassing its structure and mediating signaling pathways. More importantly, it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical determinants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies. Lastly, we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.
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Affiliation(s)
- Omkar Desai
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Moeez Rathore
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Christina S. Boutros
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Michel'le Wright
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Elizabeth Bryson
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Kimberly Curry
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Rui Wang
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
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Garrett JT, Tendler S, Feroz W, Kilroy MK, Yu H. Emerging importance of HER3 in tumorigenesis and cancer therapy. Nat Rev Clin Oncol 2025; 22:348-370. [PMID: 40087402 DOI: 10.1038/s41571-025-01008-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2025] [Indexed: 03/17/2025]
Abstract
HER3 is a member of the HER/ErbB family of receptor tyrosine kinases, together with EGFR (HER1), HER2 and HER4. Despite having only weak intrinsic kinase activity, HER3 can contribute to oncogenic signalling via ligand-induced heterodimerization with other HER family members. Evidence indicates that HER3 is altered or aberrantly expressed across a variety of tumour types and can be associated with poor clinical outcomes. Whereas anticancer agents targeting EGFR and HER2 have been approved for decades, no drug targeting HER3 had been approved until very recently. Initial targeting of HER3 with monoclonal antibodies as single agents or in combination with other therapeutics produced disappointing clinical results. Subsequently, efforts have been made to target HER3 with novel agents such as antibody-drug conjugates and bispecific antibodies, with promising efficacy observed in several trials encompassing various tumour types. In December 2024, the HER3 × HER2 bispecific antibody zenocutuzumab was granted FDA Accelerated Approval for the treatment of non-small-cell lung cancers or pancreatic cancers harbouring fusions involving NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1. In this Review, we provide an essential guide to HER3 signalling and oncogenesis, HER3 expression in cancer and its prognostic implications, oncogenic HER3 somatic mutations as well as rare NRG1 fusions that might depend on HER3 signalling, and the roles of HER3 in resistance to cancer therapies. We also highlight efforts to target HER3 with diverse therapeutic strategies and the potential interplay between HER3 and the antitumour immune response.
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Affiliation(s)
- Joan T Garrett
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
| | - Salomon Tendler
- Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wasim Feroz
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
| | - Mary Kate Kilroy
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
| | - Helena Yu
- Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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3
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Satake T, Morizane C, Okada M, Nishioka M, Hiraoka N, Nara S, Kakegawa T, Kobayashi M, Koyama K, Esaki M, Okusaka T. Prevalence of HER3 Expression in Pancreatic Cancer Patients Treated With Systemic Chemotherapy. Cancer Med 2024; 13:e70474. [PMID: 39651731 PMCID: PMC11626478 DOI: 10.1002/cam4.70474] [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: 08/05/2024] [Revised: 11/09/2024] [Accepted: 11/24/2024] [Indexed: 12/11/2024] Open
Abstract
BACKGROUND Although activation of human epidermal growth factor receptor 3 (HER3) is linked to resistance to targeted therapies in several cancer types, the HER3 expression profile during pancreatic cancer treatment remains unknown. AIMS We evaluated the HER3 expression status after chemotherapy for pancreatic cancer and its association with clinicopathological features and clinical outcomes. MATERIALS & METHODS We included patients with pancreatic cancer who underwent chemotherapy and whose post-treatment archival tissue specimens were collected. HER3 expression was retrospectively assessed by immunohistochemistry scoring (0, 1+, 2+, and 3+) of the membranous staining intensity. RESULTS HER3 expression after chemotherapy was evaluated in 41 patients, with matched-pair analysis in five patients before and after chemotherapy. HER3 expression was observed in most of the patients after chemotherapy, demonstrating IHC scores of ≥ 1+ and ≥ 2+ in 40 (98%) and 26 (63%) of 41 patients, respectively. Of the 38 patients with adenocarcinoma, the median overall survival in the HER3 (2+/3+) and HER3 (0/1+) groups was 21.0 and 17.1 months, respectively. The comparison of HER3 expression before and after chemotherapy performed in five cases revealed that scores changed from 2+/3+ to 0/1+ in one case, 0/1+ to 2+/3+ in another case, and remained at 2+/3+ in three cases. Cancer genome profiling tests in eight cases found no HER3 amplification or mutation, and seven of these cases had adenocarcinomas with KRAS and TP53 mutations. CONCLUSION A high prevalence of HER3 expression was observed in pancreatic cancer patients after chemotherapy. Our findings indicate that HER3 is a potential therapeutic target for pancreatic cancer, deserving further clinical investigation.
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Affiliation(s)
- Tomoyuki Satake
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center Hospital EastKashiwaJapan
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center HospitalTokyoJapan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center HospitalTokyoJapan
| | - Mao Okada
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center HospitalTokyoJapan
| | - Mariko Nishioka
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center HospitalTokyoJapan
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical LaboratoriesNational Cancer Center HospitalTokyoJapan
| | - Satoshi Nara
- Department of Hepatobiliary and Pancreatic SurgeryNational Cancer Center HospitalTokyoJapan
| | - Tomoya Kakegawa
- Translational Research Laboratories, Daiichi Sankyo Co. Ltd.TokyoJapan
| | - Maki Kobayashi
- Translational Research Laboratories, Daiichi Sankyo Co. Ltd.TokyoJapan
| | - Kumiko Koyama
- Translational Research Laboratories, Daiichi Sankyo Co. Ltd.TokyoJapan
| | - Minoru Esaki
- Department of Hepatobiliary and Pancreatic SurgeryNational Cancer Center HospitalTokyoJapan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center HospitalTokyoJapan
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Chen Y, Lu A, Hu Z, Li J, Lu J. ERBB3 targeting: A promising approach to overcoming cancer therapeutic resistance. Cancer Lett 2024; 599:217146. [PMID: 39098760 DOI: 10.1016/j.canlet.2024.217146] [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: 03/26/2024] [Revised: 07/21/2024] [Accepted: 07/29/2024] [Indexed: 08/06/2024]
Abstract
Human epidermal growth factor receptor-3 (ERBB3) is a member of the ERBB receptor tyrosine kinases (RTKs) and is expressed in many malignancies. Along with other ERBB receptors, ERBB3 is associated with regulating normal cell proliferation, apoptosis, differentiation, and survival, and has received increased research attention for its involvement in cancer therapies. ERBB3 expression or co-expression levels have been investigated as predictive factors for cancer prognosis and drug sensitivity. Additionally, the association between the elevated expression of ERBB3 and treatment failure in cancer therapy further established ERBB3-targeting therapy as a crucial therapeutic approach. This review delves into the molecular mechanisms of ERBB3-driven resistance to targeted therapeutics against ERBB2 and EGFR and other signal transduction inhibitors, endocrine therapy, chemotherapy, and radiotherapy. Using preclinical and clinical evidence, we synthesise and explicate how various aspects of aberrant ERBB3 activities-such as compensatory activation, signal crosstalk interactions, dysregulation in the endocytic pathway, mutations, ligand-independent activation, intrinsic kinase activity, and homodimerisation-can lead to resistance development and/or treatment failures. Several ERBB3-directed monoclonal antibodies, bispecific antibodies, and the emerging antibody-drug conjugate demonstrate encouraging clinical outcomes for improving therapeutic efficacy and overcoming resistance, especially when combined with other anti-cancer approaches. More research efforts are needed to identify appropriate biomarkers tailored for ERBB3-targeted therapies.
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Affiliation(s)
- Yutao Chen
- Auckland Bioengineering Institute, University of Auckland, Auckland, 1142, New Zealand
| | - Anni Lu
- Pinehurst School, Albany, Auckland, New Zealand
| | - Zhangli Hu
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Jinyao Li
- College of Life Sciences, Xijiang University, Urumqi, China
| | - Jun Lu
- Auckland Bioengineering Institute, University of Auckland, Auckland, 1142, New Zealand; College of Food Engineering and Nutrition Sciences, Shaanxi Normal University, Xi'an, 710119, Shaanxi Province, China; College of Food Science and Technology, Nanchang University, Nanchang, 330031, Jiangxi Province, China; Department of Food and Agriculture Technology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, Jiaxing, 314006, China.
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Theocharopoulos C, Ziogas IA, Douligeris CC, Efstathiou A, Kolorizos E, Ziogas DC, Kontis E. Antibody-drug conjugates for hepato-pancreato-biliary malignancies: "Magic bullets" to the rescue? Cancer Treat Rev 2024; 129:102806. [PMID: 39094332 DOI: 10.1016/j.ctrv.2024.102806] [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: 05/19/2024] [Revised: 07/17/2024] [Accepted: 07/28/2024] [Indexed: 08/04/2024]
Abstract
Hepato-Pancreato-Biliary (HPB) malignancies constitute a highly aggressive group of cancers that have a dismal prognosis. Patients not amenable to curative intent surgical resection are managed with systemic chemotherapy which, however, confers little survival benefit. Antibody-Drug Conjugates (ADCs) are tripartite compounds that merge the intricate selectivity and specificity of monoclonal antibodies with the cytodestructive potency of attached supertoxic payloads. In view of the unmet need for drugs that will enhance the survival rates of HPB cancer patients, the assessment of ADCs for treating HPB malignancies has become the focus of extensive clinical and preclinical investigation, showing encouraging preliminary results. In the current review, we offer a comprehensive overview of the growing body of evidence on ADC approaches tested for HPB malignancies. Starting from a concise discussion of the functional principles of ADCs, we summarize here all available data from preclinical and clinical studies evaluating ADCs in HPB cancers.
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Affiliation(s)
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | | | | | | | - Dimitrios C Ziogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens 11527, Greece
| | - Elissaios Kontis
- Department of Surgery, Metaxa Cancer Hospital, Piraeus 18537, Greece
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Zhou G, Yang L, Lu Y, Lu G. Prognostic value of hemoglobin to red blood cell distribution width ratio in pancreatic ductal adenocarcinoma: a retrospective study. BMC Gastroenterol 2024; 24:288. [PMID: 39192176 DOI: 10.1186/s12876-024-03381-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 08/22/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND Previous studies have identified the hemoglobin (Hb) to red blood cell distribution width (RDW) ratio (HRR) is associated with the prognosis of a variety of malignant tumors. However, the relationship between HRR and pancreatic ductal adenocarcinoma (PDAC) prognosis remains unexplored. This study aims to ascertain the prognostic significance of HRR in PDAC patients. METHODS In a retrospective analysis, 128 PDAC patients undergoing initial surgical resection at Ningbo Medical Center Lihuili Hospital between January 2016 and September 2021 were included. Based on receiver operating characteristic curve-derived cut-off values, participants were categorized into low and high HRR groups. The correlation between HRR and patient prognosis was subsequently examined. RESULTS Significant disparities in age, Hb levels, RDW, tumor locality, surgical intervention, and postoperative chemotherapy were observed between the two groups (P < 0.05). Notably, the low HRR cohort exhibited inferior disease-free survival (DFS) and overall survival (OS) rates (P = 0.002 for both). Univariate analysis indicated that male gender, adjacent tissue invasion, TNM stages III/IV, non-O blood types, low HRR, and lack of postoperative chemotherapy were linked to adverse DFS and OS outcomes (P < 0.05). Multivariate analysis further delineated low HRR as an independent predictor of poor DFS and OS outcomes (HR: 1.520, 95% CI: 1.028-2.247, P = 0.036; HR: 1.537, 95% CI: 1.034-2.284, P = 0.034, respectively). CONCLUSION Our findings suggest that a lower HRR is indicative of poorer DFS and OS in PDAC patients, underscoring its potential utility as a prognostic biomarker for this population.
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Affiliation(s)
- Guanbao Zhou
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Liang Yang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yangfang Lu
- Department of Radiotherapy, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Genjie Lu
- Department of Blood Transfusion, Ningbo Medical Center Lihuili Hospital, Ningbo University, 1111 Jiangnan road, Ningbo, China.
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Majumder A. HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer. Cells 2023; 12:2517. [PMID: 37947595 PMCID: PMC10648638 DOI: 10.3390/cells12212517] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/14/2023] [Accepted: 10/20/2023] [Indexed: 11/12/2023] Open
Abstract
Human epidermal growth factor receptor 3 (HER3) is the only family member of the EGRF/HER family of receptor tyrosine kinases that lacks an active kinase domain (KD), which makes it an obligate binding partner with other receptors for its oncogenic role. When HER3 is activated in a ligand-dependent (NRG1/HRG) or independent manner, it can bind to other receptors (the most potent binding partner is HER2) to regulate many biological functions (growth, survival, nutrient sensing, metabolic regulation, etc.) through the PI3K-AKT-mTOR pathway. HER3 has been found to promote tumorigenesis, tumor growth, and drug resistance in different cancer types, especially breast and non-small cell lung cancer. Given its ubiquitous expression across different solid tumors and role in oncogenesis and drug resistance, there has been a long effort to target HER3. As HER3 cannot be targeted through its KD with small-molecule kinase inhibitors via the conventional method, pharmaceutical companies have used various other approaches, including blocking either the ligand-binding domain or extracellular domain for dimerization with other receptors. The development of treatment options with anti-HER3 monoclonal antibodies, bispecific antibodies, and different combination therapies showed limited clinical efficiency for various reasons. Recent reports showed that the extracellular domain of HER3 is not required for its binding with other receptors, which raises doubt about the efforts and applicability of the development of the HER3-antibodies for treatment. Whereas HER3-directed antibody-drug conjugates showed potentiality for treatment, these drugs are still under clinical trial. The currently understood model for dimerization-induced signaling remains incomplete due to the absence of the crystal structure of HER3 signaling complexes, and many lines of evidence suggest that HER family signaling involves more than the interaction of two members. This review article will significantly expand our knowledge of HER3 signaling and shed light on developing a new generation of drugs that have fewer side effects than the current treatment regimen for these patients.
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Affiliation(s)
- Avisek Majumder
- Department of Medicine, University of California, San Francisco, CA 94158, USA
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Balaban DV, Marin FS, Manucu G, Zoican A, Ciochina M, Mina V, Patoni C, Vladut C, Bucurica S, Costache RS, Ionita-Radu F, Jinga M. Clinical characteristics and outcomes in carbohydrate antigen 19-9 negative pancreatic cancer. World J Clin Oncol 2022; 13:630-640. [PMID: 36157158 PMCID: PMC9346420 DOI: 10.5306/wjco.v13.i7.630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/19/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of death from cancer worldwide. Tumor markers like carbohydrate antigen 19-9 (CA 19-9) have been proven valuable as a diagnostic tool and a predictor for tumor staging and response to therapy. AIM To delineate the phenotype of normal CA 19-9 PDAC according to clinical features, disease staging and prognosis as compared with high CA 19-9 PDAC cases. METHODS We performed a retrospective single-center analysis of all PDAC cases admitted in our Gastroenterology department over a period of 30 mo that were diagnosed by endoscopic ultrasound-guided tissue acquisition. Patients were divided into two groups according to CA 19-9 levels over a threshold of 37 U/mL. We performed a comparison between the two groups with regard to demographic and clinical data, biomarkers, tumor staging and 6-mo survival. RESULTS Altogether 111 patients were recruited with 29 having documented normal CA 19-9 (< 37 U/mL). In the CA 19-9 negative group of patients, 20.68% had elevated levels of both CEA and CA 125, 13.79% for CA 125 only whilst 17.24% for CEA only. The two groups had similar demographic characteristics. Abdominal pain was more frequently reported in positive vs negative CA 19-9 PDAC cases (76.83% vs 55.17%), while smoking was slightly more prevalent in the latter group (28.04% vs 31.03%). Tumors over 2 cm were more frequently seen in the positive CA 19-9 group, reflecting a higher proportion of locally advanced and metastatic neoplasia (87.7% vs 79.3%). Six-month survival was higher for the negative CA 19-9 group (58.62% vs 47.56%). CONCLUSION Elevated CA 19-9 at diagnosis seems to be associated with a more pronounced symptomatology, high tumor burden and poor prognosis compared to negative CA 19-9 PDAC cases. CEA and CA 125 can be adjunctive useful markers for PDAC, especially in CA 19-9 negative cases.
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Affiliation(s)
- Daniel Vasile Balaban
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Flavius Stefan Marin
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, Paris 75014, France
| | - George Manucu
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Andreea Zoican
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Marina Ciochina
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Victor Mina
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Cristina Patoni
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Catalina Vladut
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Prof Dr. Agrippa Ionescu Clinical Emergency Hospital, Bucharest 020021, Romania
| | - Sandica Bucurica
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Raluca Simona Costache
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Florentina Ionita-Radu
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Mariana Jinga
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
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Dobre M, Herlea V, Vlăduţ C, Ciocîrlan M, Balaban VD, Constantinescu G, Diculescu M, Milanesi E. Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma. Cells 2021; 10:1856. [PMID: 34440625 PMCID: PMC8391367 DOI: 10.3390/cells10081856] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway. METHOD We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue). RESULTS We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues. CONCLUSIONS We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.
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Affiliation(s)
- Maria Dobre
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (E.M.)
| | - Vlad Herlea
- Department of Pathology, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Cătălina Vlăduţ
- Department of Gastroenterology, “Prof Dr Agrippa Ionescu” Clinical Emergency Hospital, 011356 Bucharest, Romania;
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
| | - Mihai Ciocîrlan
- Department of Gastroenterology, “Prof Dr Agrippa Ionescu” Clinical Emergency Hospital, 011356 Bucharest, Romania;
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
| | - Vasile Daniel Balaban
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
- Department of Gastroenterology, Carol Davila Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Gabriel Constantinescu
- Department of Gastroenterology, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania;
| | - Mircea Diculescu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
- Department of Gastroenterology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Elena Milanesi
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (E.M.)
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Momeny M, Esmaeili F, Hamzehlou S, Yousefi H, Javadikooshesh S, Vahdatirad V, Alishahi Z, Mousavipak SH, Bashash D, Dehpour AR, Tavangar SM, Tavakkoly-Bazzaz J, Haddad P, Kordbacheh F, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH. The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cell Oncol (Dordr) 2019; 42:491-504. [PMID: 31025257 DOI: 10.1007/s13402-019-00448-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2019] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. METHODS Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. RESULTS We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. CONCLUSIONS Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.
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Affiliation(s)
- Majid Momeny
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
| | - Fatemeh Esmaeili
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Hamzehlou
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Sepehr Javadikooshesh
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vasimeh Vahdatirad
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zivar Alishahi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh H Mousavipak
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad R Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed M Tavangar
- Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoly-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Peiman Haddad
- Radiation Oncology Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Kordbacheh
- Cancer and Vascular Biology Group, ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Kamran Alimoghaddam
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ardeshir Ghavamzadeh
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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11
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Suga J, Izumiyama K, Tanaka N, Saji S. Estradiol promotes rapid degradation of HER3 in ER-positive breast cancer cell line MCF-7. Biochem Biophys Rep 2018; 16:103-109. [PMID: 30417127 PMCID: PMC6205365 DOI: 10.1016/j.bbrep.2018.10.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/21/2018] [Accepted: 10/09/2018] [Indexed: 02/07/2023] Open
Abstract
HER3, a member of the receptor tyrosine kinase super family, is overexpressed in a number of cancers, and is associated with malignant phenotypes. Control of the protein stability of the membrane, as well as nuclear receptors, has been known to be an important process affecting tumor cells; however, their relationships have yet to be elucidated. In this study, we demonstrate that estradiol promotes rapid degradation of HER3 via the proteasome pathway in ER-positive breast cancer, MCF-7. ER prevented HER3 degradation, and knockdown of ER expression by si-RNA promoted rapid degradation of HER3. Breakdown of HER3 and ER were regulated by a ubiquitin ligase Nedd4-1 in the presence of estradiol stimulation. We speculate that estradiol quickly degrades ER, making HER3 accessible by Nedd4-1, and leads to the rapid degradation of HER3. In addition, knockdown of ubiquitin ligase Nedd4-1 enhances estradiol induced cell proliferation. These results indicate that HER3 and Nedd4-1 in ER-positive breast cancers might be an important therapeutic target.
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Affiliation(s)
- Junko Suga
- Department of Medical Oncology, Fukushima Medical University, 1 Hikariga-oka, Fukushima-shi, Fukushima 960-1295, Japan
| | - Keiko Izumiyama
- Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori, Miyagi 981-1293, Japan
| | - Nobuyuki Tanaka
- Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori, Miyagi 981-1293, Japan.,Division of Cancer Immunobiology, Department of Cancer Medical Science, Tohoku University Graduate School of Medicine, 2-1 Seiryo Aobaku, Sendai 980-0875, Japan
| | - Shigehira Saji
- Department of Medical Oncology, Fukushima Medical University, 1 Hikariga-oka, Fukushima-shi, Fukushima 960-1295, Japan
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12
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McKnight BN, Kuda-Wedagedara ANW, Sevak KK, Abdel-Atti D, Wiesend WN, Ku A, Selvakumar D, Carlin SD, Lewis JS, Viola-Villegas NT. Imaging EGFR and HER3 through 89Zr-labeled MEHD7945A (Duligotuzumab). Sci Rep 2018; 8:9043. [PMID: 29899472 PMCID: PMC5998059 DOI: 10.1038/s41598-018-27454-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 06/04/2018] [Indexed: 02/07/2023] Open
Abstract
Tumor resistance to treatment paved the way toward the development of single agent drugs that target multiple molecular signatures amplified within the malignancy. The discovered crosstalk between EGFR and HER3 as well as the role of HER3 in mediating EGFR resistance made these two receptor tyrosine kinases attractive targets. MEHD7945A or duligotuzumab is a single immunotherapy agent that dually targets both molecular signatures. In this study, a positron emission tomography (PET) companion diagnostic to MEHD7945A is reported and evaluated in pancreatic cancer. Tumor accretion and whole body pharmacokinetics of 89Zr-MEHD7945A were established. Specificity of the probe for EGFR and/or HER3 was further examined.
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Affiliation(s)
- Brooke N McKnight
- Department of Oncology, Karmanos Cancer Institute, 4100 John R. Street, Detroit, MI, 48201, USA
| | | | - Kuntal K Sevak
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Dalya Abdel-Atti
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Wendy N Wiesend
- Department of Anatomic Pathology, Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI, 48073, USA
| | - Anson Ku
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | | | - Sean D Carlin
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
- Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
- Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA
| | - Nerissa T Viola-Villegas
- Department of Oncology, Karmanos Cancer Institute, 4100 John R. Street, Detroit, MI, 48201, USA.
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
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13
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Bensch F, Lamberts LE, Smeenk MM, Jorritsma-Smit A, Lub-de Hooge MN, Terwisscha van Scheltinga AGT, de Jong JR, Gietema JA, Schröder CP, Thomas M, Jacob W, Abiraj K, Adessi C, Meneses-Lorente G, James I, Weisser M, Brouwers AH, de Vries EGE. 89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors. Clin Cancer Res 2017; 23:6128-6137. [PMID: 28733442 DOI: 10.1158/1078-0432.ccr-17-0311] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 05/30/2017] [Accepted: 07/18/2017] [Indexed: 01/24/2023]
Abstract
Purpose: We evaluated biodistribution and tumor targeting of 89Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received 89Zr-lumretuzumab and underwent positron emission tomography (PET). In part A, 89Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results: Optimal PET conditions were found to be 4 and 7 days after administration of 89Zr-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5), and 24.6% (±20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab.Conclusions: PET imaging showed biodistribution and tumor-specific 89Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. Clin Cancer Res; 23(20); 6128-37. ©2017 AACR.
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Affiliation(s)
- Frederike Bensch
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Laetitia E Lamberts
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Michaël M Smeenk
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Annelies Jorritsma-Smit
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Marjolijn N Lub-de Hooge
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands.,Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, the Netherlands
| | | | - Johan R de Jong
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Jourik A Gietema
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Carolien P Schröder
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Marlene Thomas
- Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Wolfgang Jacob
- Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Keelara Abiraj
- Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Celine Adessi
- Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | | | - Ian James
- A4P Consulting Ltd, Sandwich, United Kingdom
| | - Martin Weisser
- Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Adrienne H Brouwers
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Elisabeth G E de Vries
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands.
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14
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Li Q, Zhang R, Yan H, Zhao P, Wu L, Wang H, Li T, Cao B. Prognostic significance of HER3 in patients with malignant solid tumors. Oncotarget 2017; 8:67140-67151. [PMID: 28978022 PMCID: PMC5620162 DOI: 10.18632/oncotarget.18007] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 03/21/2017] [Indexed: 02/02/2023] Open
Abstract
Human epidermal growth factor receptor 3 (HER3) is closely involved in tumor progression and is an important target of therapy. To evaluate the prognostic significance of HER3 in malignant solid tumors, we searched the PUBMED, EMBASE and CNKI databases for relevant studies written in English or Chinese up to December 2015. Fifteen studies comprising 2964 patients were identified. The HER3+ rate ranged from 9.0-75.1 % in malignant solid tumors: 30.3-75.1 % in breast cancers, 51.1-74.5 % in colorectal cancers, 13.7-59.0 % in gastric cancers, and 54.5-74.4 % in cervical cancers. For patients with a malignant solid tumor, the death risk was higher for those with a HER3+ tumor than for those with a HER3− tumor (HR 1.60, 95% CI: 1.27 - 2.02, P < 0.001). Subgroup analysis revealed this was also the case for patients with digestive or gastric cancer (HR 1.78, P < 0.001; HR 2.18, P < 0.001). By contrast, HER3 had no prognostic significance in colorectal or breast cancer (HR 1.52, P = 0.296; HR 1.23, P = 0.108). HER3+ is thus associated with poor survival in overall and in gastric cancer. The prognostic significance of HER3+ in other tumors is uncertain and deserves further study.
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Affiliation(s)
- Qin Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - RuiXue Zhang
- Department of Internal Medicine, The First Hospital, Tsinghua University, Beijing 100016, China
| | - Han Yan
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - PengFei Zhao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Li Wu
- Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
| | - Hui Wang
- Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
| | - Teng Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.,Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.,Beijing Digestive Diseases Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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15
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Prognostic impact of HER3 based on protein and mRNA expression in high-grade serous ovarian carcinoma. Virchows Arch 2016; 470:143-151. [PMID: 27913862 DOI: 10.1007/s00428-016-2050-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 11/01/2016] [Accepted: 11/21/2016] [Indexed: 01/08/2023]
Abstract
HER3 is a member of the epidermal growth factor family and was predominantly described as a negative prognostic factor in various solid tumors as well as in ovarian cancer. In this study, we investigated HER3 on protein and mRNA expression in histologically defined subtypes of ovarian cancer looking for an influence on patient's survival. Altogether, we examined HER3 in ovarian high-grade serous (HGSC, n = 320), low-grade serous (LGSC, n = 55), endometrioid (EC, n = 33), and clear cell (CCC, n = 48) carcinomas using immunohistochemistry (IHC) and quantitative real-time reverse transcription PCR (qRT-PCR). Univariate and multivariate analyses were performed to explore the association between HER3 and overall survival (OS) as well as progression-free survival (PFS). In HGSC, high HER3 mRNA expression was a favorable prognostic factor for PFS (P = 0.008) and OS (P = 0.052), while for high HER3 protein expression, a trend towards better survival was seen (OS P = 0.064; PFS P = 0.099). A subgroup of HGSC with negative HER3 staining and negative HER3 mRNA levels showed most unfavorable OS and PFS (P = 0.002 and P = 0.004, respectively). Using the multivariate Cox regression model, HER3 was predictive for prolonged PFS (HR, 0.48; 95% CI, 0.26-0.88; P = 0.018). All in all, we cannot confirm the reported negative prognostic impact of HER3 expression in high-grade serous ovarian carcinoma and moreover find a rather positive prognostic implication of HER3 in this major ovarian cancer histological subtype.
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16
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Li Q, Zhang L, Li X, Yan H, Yang L, Li Y, Li T, Wang J, Cao B. The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer : HER1-4 protein expression and prognosis in pancreatic cancer. BMC Cancer 2016; 16:910. [PMID: 27871278 PMCID: PMC5117489 DOI: 10.1186/s12885-016-2889-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 10/25/2016] [Indexed: 01/25/2023] Open
Abstract
Background Prognostic factors aid in the stratification and treatment of cancer. This study evaluated the prognostic significance of human epidermal growth factor receptor (HER) family members (HER1–4) expression in patients with operable pancreatic cancer. Methods The expression of individual HER proteins in patient tissue specimens was detected by immunohistochemistry staining. Patient follow-up time was between 1.0 and 78.1 months. Results Positive expression of HER1, HER2, HER3 and HER4 was detected in 41.4, 60.0, 24.3 and 65.7% of cases, respectively. Kaplan–Meier analysis revealed that HER3 positive expression was associated with decreased median survival time (12.0 vs. 25.6 months for HER3 positive and negative groups, respectively; P = 0.013). Cox’s regression confirmed that positive HER3 expression was an independent predictor of poor survival (RR = 3.684, P = 0.001). In contrast, HER4 negative patients had a significantly decreased median survival time when compared with HER4 positive patients (11.4 vs. 25.6 months, respectively; P = 0.027). However, HER4 was not an independent predictor of survival. No significant association between HER1 or HER2 expression and survival was observed (P = 0.626 & P = 0.859, respectively). Conclusions HER3 is an independent prognostic marker for patients with operable pancreatic cancer. HER4 may also be of potential prognostic value in this disease and deserves further attention.
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Affiliation(s)
- Qin Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Lei Zhang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - XiuHong Li
- Research Experiments Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Han Yan
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Liuting Yang
- Department of Biochemistry and Molecular Biology, Basic Medical College, Shanxi Medical University, Taiyuan, China
| | - Yingying Li
- Department of Pathology and Pathophysiology, Basic Medical College, Capital Medical University, Beijing, China
| | - Teng Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Jing Wang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. .,Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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17
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Hirakawa T, Yashiro M, Doi Y, Kinoshita H, Morisaki T, Fukuoka T, Hasegawa T, Kimura K, Amano R, Hirakawa K. Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia. PLoS One 2016; 11:e0159912. [PMID: 27487118 PMCID: PMC4972430 DOI: 10.1371/journal.pone.0159912] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 07/11/2016] [Indexed: 12/21/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs), the expression of insulin-like growth factor-1 (IGF1) and IGF1 receptor (IGF1R) was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9) was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2) and hypoxia (1% O2). IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.
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Affiliation(s)
- Toshiki Hirakawa
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masakazu Yashiro
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan
- * E-mail:
| | - Yosuke Doi
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Haruhito Kinoshita
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tamami Morisaki
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tatsunari Fukuoka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tsuyoshi Hasegawa
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kenjiro Kimura
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ryosuke Amano
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kosei Hirakawa
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
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18
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Lakshmanan I, Seshacharyulu P, Haridas D, Rachagani S, Gupta S, Joshi S, Guda C, Yan Y, Jain M, Ganti AK, Ponnusamy MP, Batra SK. Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells. Oncotarget 2016; 6:21085-99. [PMID: 26035354 PMCID: PMC4673252 DOI: 10.18632/oncotarget.3912] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/05/2015] [Indexed: 01/28/2023] Open
Abstract
Several studies have demonstrated that MUC4 is involved in progression and metastasis of pancreatic cancer (PC). Here, we report that HER3/MUC4 interaction in HER2 low cells is critical in driving pancreatic tumorigenesis. Upon HER2 knockdown, we observed elevated expression of HER3 and MUC4 and their interactions, which was confirmed by immunoprecipitation and bioinformatics analyses. In paired human PC tissues, higher percentage of HER3 positivity (10/33, 30.3%; p = 0.001) was observed than HER2 (5/33, 15.1%; p = 0.031), which was further confirmed in spontaneous mice (KPC; KrasG12D; Trp53R172H/+; Pdx-Cre) tumors of different weeks. Mechanistically, increased phosphorylation of ERK and expression of PI3K and c-Myc were observed in HER2 knockdown cells, suggesting a positive role for HER3/MUC4 in HER2 low cells. Further, HER2 knockdown resulted in increased proliferation, motility and tumorigenicity of PC cells. Consistently, transient knockdown of HER3 by siRNA in HER2 knockdown cells led to decreased proliferation. These observations led us to conclude that HER3 interacts with MUC4 to promote proliferation in HER2 low PC cells. Further, deficiency of both HER2 and HER3 leads to decreased proliferation of PC cells. Hence targeting these newly identified HER3/MUC4 signals would improve the PC patients survival by intercepting MUC4 mediated oncogenic signaling.
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Affiliation(s)
- Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Dhanya Haridas
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Suprit Gupta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Suhasini Joshi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ying Yan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Apar K Ganti
- Department of Medicine, VA Nebraska Western Iowa Health Care System, Omaha, NE, USA.,Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
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Elebro J, Heby M, Warfvinge CF, Nodin B, Eberhard J, Jirström K. Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1, 2 and 3 in Periampullary Adenocarcinoma. PLoS One 2016; 11:e0153533. [PMID: 27070783 PMCID: PMC4829175 DOI: 10.1371/journal.pone.0153533] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 03/30/2016] [Indexed: 12/11/2022] Open
Abstract
Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumours with dismal prognosis, for which there is an urgent need to identify novel treatment strategies. The human epithelial growth factor receptors EGFR, HER2 and HER3 have been studied in several tumour types, and HER-targeting drugs have a beneficial effect on survival in selected types of cancer. However, these effects have not been evident in pancreatic cancer, and remain unexplored in other types of periampullary cancer. The prognostic impact of HER-expression in these cancers also remains unclear. The aim of this study was therefore to examine the expression and prognostic value of EGFR, HER2 and HER3 in periampullary cancer, with particular reference to histological subtype. To this end, protein expression of EGFR, HER2 and HER3, and HER2 gene amplification was assessed by immunohistochemistry and silver in situ hybridization, respectively, on tissue microarrays with tumours from 175 periampullary adenocarcinomas, with follow-up data on recurrence-free survival (RFS) and overall survival (OS) for up to 5 years. EGFR expression was similar in pancreatobiliary (PB) and intestinal (I) type tumours, but high HER2 and HER3 expression was significantly more common in I-type tumours. In PB-type cases receiving adjuvant gemcitabine, but not in untreated cases, high EGFR expression was significantly associated with a shorter OS and RFS, with a significant treatment interaction in relation to OS (pinteraction = 0.042). In I-type cases, high EGFR expression was associated with a shorter OS and RFS in univariable, but not in multivariable, analysis. High HER3 expression was associated with a prolonged RFS in univariable, but not in multivariable, analysis. Neither HER2 protein expression nor gene amplification was prognostic. The finding of a potential interaction between the expression of EGFR and response to adjuvant chemotherapy in PB-type tumours needs validation, and merits further study.
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Affiliation(s)
- Jacob Elebro
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
- * E-mail:
| | - Margareta Heby
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| | - Carl Fredrik Warfvinge
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| | - Björn Nodin
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| | - Jakob Eberhard
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| | - Karin Jirström
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
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HER family receptor expression and prognosis in pancreatic cancer. Int J Biol Markers 2015; 30:e327-32. [PMID: 26109364 DOI: 10.5301/jbm.5000157] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2015] [Indexed: 01/21/2023]
Abstract
BACKGROUND HER family receptors play a key role in tumor progression in several malignancies, such as colorectal, lung or breast cancer. The aims of this study were to investigate expression of HER-1, HER-2 and HER-3 in pancreatic cancer (PC) samples and evaluate the association between HER-family receptor expression and patients' clinical outcomes. METHODS Tissue samples from 91 PC patients were subjected to immunohistochemical staining to assess the expression of HER-1, HER-2 and HER-3. Semiquantitative scores of zero (no staining or staining in less than 10% of cancer cells), 1+, 2+ or 3+ were assigned to each sample based on the intensity of staining for HER receptors. Scores of 2+ or 3+ were defined as positive staining. RESULTS HER-1 overexpression was observed in 41 out of 91 samples (45.1%), while HER-2 was not overexpressed in any of the analyzed samples. HER-3 was overexpressed in 37 samples (40.7%) and was found to be associated with advanced TNM stage. In particular, HER-3 was overexpressed in 12 out of 16 stage IV patients (75%) compared with only 33.3% of stage I-III patients (p = 0.02). Among 79 patients with available survival data, the 6 patients with strong HER-3 expression (score 3+) had a shorter survival compared with remaining patients (median overall survival 6.9 months vs. 12.3 months, respectively). CONCLUSIONS HER-1 and HER-3 were found to be expressed in a significant proportion of PC patients. Strong HER-3 expression represents an indicator of poor prognosis in PC patients, being associated with advanced stage and shorter survival.
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Tang SC, Chen YC. Novel therapeutic targets for pancreatic cancer. World J Gastroenterol 2014; 20:10825-10844. [PMID: 25152585 PMCID: PMC4138462 DOI: 10.3748/wjg.v20.i31.10825] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/13/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.
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Dong Q, Yang XH, Zhang Y, Jing W, Zheng LQ, Liu YP, Qu XJ. Elevated serum CA19-9 level is a promising predictor for poor prognosis in patients with resectable pancreatic ductal adenocarcinoma: a pilot study. World J Surg Oncol 2014; 12:171. [PMID: 24890327 PMCID: PMC4064278 DOI: 10.1186/1477-7819-12-171] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 05/16/2014] [Indexed: 02/07/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers. Several studies have reported that the carbohydrate antigen 19-9 (CA19-9) level is a useful marker for predicting the prognosis for PDAC after resection. However, the cutoff value of CA19-9 used to predict prognosis varied among these reports. The aims of this study were to evaluate whether the serum CA19-9 level is a significant predictor for survival and to determine the optimal cutoff value of CA19-9 for predicting prognosis. Methods A total of 120 consecutive patients who underwent surgery for potentially resectable primary PDAC were retrospectively analyzed. The variables included the following: age, sex, the location of the tumor, the maximal tumor size, the histological differentiation, the margin status, the tumor stage, serum CA19-9 levels, and serum total bilirubin (TBil) levels. Results The overall 1-year survival rate was 62.5%. The receiver operating characteristic (ROC) curve indicated a significant result for the level of CA19-9 in predicting death within 1 year after surgery (Area under the curve (AUC), 0.612; 95% confidence interval (CI), 0.505-0.720; P = 0.040). The optimal cutoff point was 338.45 U/mL (sensitivity, 60.0%; specificity, 66.7%; accuracy, 64.2%). The strongest univariate predictor among the categorized CA19-9 values was CA19-9 greater than or equal to 338.45 U/mL. In the multivariate Cox proportional hazards mode analysis, the serum CA19-9 level, age and the histological differentiation were significant independent prognostic factors that were associated with the overall survival. Conclusions The preoperative elevated CA19-9 level is a promising independent factor for predicting a poor prognosis in PDAC, and the optimal cutoff value is 338.45 U/mL.
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Affiliation(s)
| | - Xiang-hong Yang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, P,R, China.
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The function of human epidermal growth factor receptor-3 and its role in tumors (Review). Oncol Rep 2013; 30:2563-70. [DOI: 10.3892/or.2013.2754] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 09/06/2013] [Indexed: 11/05/2022] Open
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Desai MD, Saroya BS, Lockhart AC. Investigational therapies targeting the ErbB (EGFR, HER2, HER3, HER4) family in GI cancers. Expert Opin Investig Drugs 2013; 22:341-56. [PMID: 23316969 DOI: 10.1517/13543784.2013.761972] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Gastrointestinal (GI) malignancies account for nearly one-fourth of all cancer-related deaths in the United States and approximately 30% of all cancer-related deaths worldwide. Use of combination cytotoxic therapy offers a modest improvement in survival, but the prognosis and long-term survival of most patients with GI cancer remains poor. In certain GI malignancies, therapies that target members of the HER family of receptors have positively impacted patient care. AREAS COVERED In this review, we discuss the significance of the HER family of receptors in esophagogastric, hepatobiliary, pancreatic, and colorectal cancers and explain the rationale supporting the use of monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs) to inhibit HER activation and downstream events that contribute to tumor proliferation, migration, and survival. EXPERT OPINION Despite recent advances, the treatment of GI cancers remains challenging. Therapies targeting the HER family of receptors have been extensively studied in these malignancies with inconsistent results. The rationale behind varied tumor responses with these agents remains uncertain. We believe that additional studies are needed to identify biomarkers that could help identify a population of patients who would be more responsive to a given therapy.
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Affiliation(s)
- Monica Dandona Desai
- Washington University in St. Louis, Medicine, 660 S. Euclid Ave, Box 8056, St. Louis, MO 63110, USA
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Danielsson K, Ansari D, Andersson R. Personalizing Pancreatic Cancer Medicine: What are the Challenges? Per Med 2013; 10:45-59. [DOI: 10.2217/pme.12.111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Krissi Danielsson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
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Ocana A, Vera-Badillo F, Seruga B, Templeton A, Pandiella A, Amir E. HER3 overexpression and survival in solid tumors: a meta-analysis. J Natl Cancer Inst 2012; 105:266-73. [PMID: 23221996 DOI: 10.1093/jnci/djs501] [Citation(s) in RCA: 176] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND The human epidermal growth factor receptor 3 (HER3) is an ErbB/HER family member that dimerizes with other ErbB receptors such as HER2. Numerous agents against HER3 are in clinical development despite variable data for the prognostic impact of HER3 expression. Here we report a meta-analysis of the association of HER3 expression and survival in solid tumors. METHODS PubMed was searched for studies evaluating expression of HER3 (as measured by immunohistochemistry) and overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (ORs) for death at 3 and 5 years. Data were pooled using the Mantel-Haenszel random-effect model. All statistical tests were two-sided. RESULTS Analysis included 12 studies: three that evaluated colorectal cancer, two that evaluated gastric cancer, two that evaluated breast cancer, and one each that evaluated melanoma, ovarian cancer, head and neck cancer, pancreatic cancer, and cervical cancer. The median percentage of cancers with HER3 overexpression was 42.2%. HER3 was associated with worse OS at both 3 years (OR = 2.24, 95% confidence interval [CI] = 1.77 to 2.83, P < .001) and 5 years (OR = 2.20, 95% CI = 1.75 to 2.76, P < .001). Among studies with common HER2 overexpression (breast, gastric, and ovarian cancers), the magnitude of effect of HER3 on OS was statistically significantly greater for both 3-year OS (OR = 3.12, 95% CI = 2.24 to 4.37) and 5-year OS (OR = 2.84, 95% CI = 2.09 to 3.88). CONCLUSIONS Expression of HER3 is associated with worse survival in solid tumors. The influence of HER3 may be greater in those tumors where HER2 is commonly overexpressed.
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Affiliation(s)
- Alberto Ocana
- Translational Research Unit and Medical Oncology Department, Albacete University Hospital, Albacete, Spain.
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