Non-invasive assays for protein biomarkers of cancer allow both its early diagnosis and continuous treatment monitoring. Yet, accurate point-of-care (POC) diagnostic devices for cancer diagnosis and monitoring, needed in point-of-care (POC) sites and places with limited resources, are scarce, not the least, due to their high current cost or bulky equipment necessary for analysis. Here, we show that the capacitive cellulase-linked electrochemical enzyme-linked aptamer-sorbent assay (e-ELASA) on magnetic beads (MBs) performed with airbrushed graphite (Gr) electrodes accurately and economically detects HER-2/neu, the protein biomarker of some aggressive forms of cancers and target of anticancer therapy. The disposable Gr electrodes were produced by airbrushing inexpensive graphite-powder/chitosan water inks onto polyester transparency films, producing high-capacitance electrodes, whose apparent specific capacitance ranged between 3.61 and 8.88 mF cm-2 as a function of the number of sprayed layers and graphite content in inks. The five-layer electrodes produced from 1.7 g of graphite powder (per 5 mL)/0.55 % chitosan water inks outperformed manually polished spectroscopic Gr electrodes earlier used in this label-free capacitive e-ELASA, as a result of the higher capacitive changes of the former, providing the same 0.1 fM limit of detection of HER-2/neu, in both buffer and 10 % serum, yet with a three-fold higher sensitivity. The portable and low cost airbrushed electrodes/e-ELASA set-up can be used for quick and accurate regular POC monitoring of HER-2/neu, particularly, in low and middle income settings, and, in perspective, the high-capacitance airbrushed electrodes can be adapted for other type label-free capacitive bioassays.

In clinical oncology, lack of sustained treatment response is very common in cancer patients and largely limits the efficiency of most anticancer targeted-therapies. While anti-EGFR therapeutics have been extensively employed in head and neck squamous cell carcinoma (HNSCC) management, their clinical efficacy remains limited due to unresolved resistance mechanisms. Notably, the functional role of EGFR ligand proteins in both tumor progression and therapeutic response has not been fully elucidated. Here we reveal that amphiregulin (AREG) as a potential driver of drug resistance of EGFR-targeted treatment in HNSCC patients. We identify a PDGFRβ+FAP+αSMA+ myofibroblast (myCAF) subset as the major source of AREG in tumor microenvironment. TCGA database and clinical cohort demonstrated that patients with high AREG expression exhibited significantly higher lymph node metastasis rates (59.35 %) and poorer prognosis (median 5-year survival: 2.2 years). In contrast, patients with low AREG expression showed reduced metastatic potential (metastasis rate: 45.16 %) and more favorable clinical outcomes (median 5-year survival: 4.8 years). Mechanistically, AREG promotes vascular mimicry formation via epithelial-endothelial transition of tumor cells to offer extra blood supply and metastasis channels. Further, live-cell imaging revealed that AREG induces plasma membrane stabilization of over 90 % receptor proteins while concurrently enhancing receptor recycling, driving EGFR inhibitor resistance. Collectively, our study reveals the crucial role of AREG in tumor landscape, informing a new predictive biomarker of EGFR inhibitor efficiency as well as a new potential therapeutic target of HNSCC.

Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) poses a significant challenge to enhancing the efficacy of cancer treatments. Beyond the cellular mechanisms intrinsic to tumor cells, the modulation of the tumor immune microenvironment is crucial in dictating the responsiveness to pharmacological interventions. Thus, there is a pressing need to elucidate the intricate interplay between PARPi and antitumor immune responses and to develop an optimized combinatorial therapeutic approach. In this study, using matched tumor samples before and after neoadjuvant monotherapy with the PARPi niraparib in a prospective clinical trial (NCT04507841), we observed a significant increase in natural killer (NK) cell infiltration post-treatment. However, this was not accompanied by the expected enhancement in their cytotoxic functions. This observation underscores the necessity to optimize the antitumor potential of NK cells by enhancing their cytotoxic capabilities. Upon exposure to niraparib, tumor cells, particularly those with wild-type EGFR, exhibited a pronounced upregulation of human leukocyte antigen G (HLA-G), an immune checkpoint impeding NK cell functions. Niraparib promotes EGFR internalization, which in turn diminishes AKT/mTOR signaling, leading to the increased transcriptional activity of the transcription factor EB (TFEB) and subsequent enhancement of HLA-G expression. The combination of niraparib with HLA-G blockade not only augmented NK cell-mediated tumor lysis in vitro but also synergistically inhibited tumor growth in humanized patient-derived xenograft models. Collectively, our results shed light on a previously unrecognized immune evasion mechanism and offer a compelling argument for the integration of HLA-G blockade with PARPi in cancer therapy.

Epidermal growth factor receptor (EGFR) is a potential target for anticancer therapies and plays a crucial role in cell growth, survival, and metastasis. EGFR gene mutations trigger aberrant signaling, leading to non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) effectively target these mutations to treat NSCLC. While the first three generations of EGFR TKIs have been proven effective, the emergence of the EGFR-C797S resistance mutation poses a new challenge. To address this, various synthetic EGFR TKIs have been developed. In this review, we have summarized the EGFR TKIs reported in the past five years, focusing on their clinical outcomes and structure-activity relationship analysis. We have also explored binding modes and interactions between the binding pocket and ligands to provide insights into the mechanisms of these inhibitors, which contribute to advancements in targeted cancer therapy. Additionally, artificial Intelligence-driven methods, including recursive neural networks and reinforcement learning, have revolutionized EGFR inhibitor design by facilitating rapid screening, predicting EGFR mutations, and novel compound generation.

Colorectal cancer is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. Despite an increase in overall survival throughout the years, the prognosis of metastatic colorectal cancer remains poor. Until recently, its treatment was based on the use of standard chemotherapy combined with, anti-epidermal growth factor receptor (for RAS wild-type tumors) or anti-vascular endothelial growth factor, or immunotherapy for tumors with mismatch repair deficiency. Over the last years, precision medicine has become a challenge in oncology and there has been an increasing development of biomarker-driven therapies for metastatic colorectal cancer leading to better outcomes for specific molecular subgroups of patients. Human epidermal growth factor receptor 2 (HER2) amplification/overexpression has been identified in about 6 % of patients with RAS wild-type metastatic CRC and established as an important and drugable biomarker. Its prognostic and predictive implications are still debated but HER2 becoming a therapeutic target with promising results of anti-HER2 therapies for HER2-positive metastatic CRC. Multiple HER2-targeted regimens are now part of National Comprehensive Cancer Network and European Society for Medical Oncology guidelines with two recent Food and Drug Administration approvals for previously treated HER2-positive metastatic colorectal cancer for tucatinib (in combination with trastuzumab) and for trastuzumab-deruxtecan in patients with previously treated HER2-positive metastatic colorectal cancer. This review explores the prognostic and predictive value of HER2 as a biomarker in CRC, describing its molecular structure, the clinical characteristics of patients with HER2 alterations, diagnostic approaches and the most relevant clinical trials assessing its current and future role as a therapeutic target in metastatic colorectal cancer.

Receptor-mediated targeted drug delivery has emerged as a pivotal strategy in cancer therapy, offering precision and specificity in combating malignant diseases while minimizing systemic toxicity. This review explores the multifaceted role of receptors in cancer biology, emphasizing their contributions to cancer progression, metastasis, and their potential as therapeutic targets. Ligand-based targeting approaches highlight the utility of small molecules, peptides, and antibodies, as well as the development of novel targeting ligands. A critical focus is placed on engineering receptor-targeted nanoparticles and advanced drug delivery systems. Innovations in dual-targeting strategies and the targeted delivery to the tumour microenvironment (TME) and metastatic niches are discussed, underscoring their potential to enhance therapeutic efficacy. Additionally, receptor-targeted imaging is reviewed for its dual role in diagnosis and real-time treatment monitoring. To address the challenges of side effects and off-target toxicity, strategies that minimize these risks while targeting overexpressed receptors in solid tumours are explored. Finally, the review outlines future directions in receptor-targeted cancer therapy, emphasizing the need for interdisciplinary research to refine these strategies further. This comprehensive analysis aims to provide a roadmap for advancing receptor-based therapeutic approaches, ultimately improving outcomes for cancer patients.

Breast cancer is the most frequent non-dermatologic malignancy in women. Breast cancer is characterized by the expression of the human epidermal growth factor receptor type 2 (HER2), and the presence or lack of estrogen receptor (ER) and progesterone receptor (PR) expression. HER2 overexpression is reported in about 20 to 25% of breast cancer patients, which is usually linked to cancer progression, metastases, and poor survival. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the gold standards for determining HER2 status, even though IHC has largely focused on quantifying HER2+ status versus "other" HER2 status (including variants with low or no expression). Recent findings regarding the beneficial therapeutic effects of anti-HER2 monoclonal antibodies (mAb) in HER2low metastatic patients lead to changes in the classic definition of advanced breast cancer, and methods for precise assessment of HER2 status are being developed. As a result, various radiolabeled HER-targeted mAbs and antibody fragments have been designed to avoid repeated biopsies with potential bias due to tumor heterogeneity, including single-chain variable fragment (scFv), F(ab')2, affibody, and nanobody. These small targeting radiotracers displayed favorable biodistributions, clearance, and stability, allowing for higher image quality, shorter circulation half-life, and lower immunogenicity. This study aimed to comprehensively review the application of radiolabeled anti-HER2 antibody fragments in breast cancer in vivo imaging and provide a better understanding of targeted HER2 quantification.

Our study investigated the predictive efficacy of AI-based Machine Learning (ML) model for determining HER2 status in a population of 3424 breast cancer patients. Multivariate logistic regression analysis identified several independent variables that were predictive of HER2 positivity, namely age ≤ 40 years, tumor multicentricity, high tumor grade, high-grade DCIS, N3 stage disease, and negative ER status (p < 0.05). These findings suggest that patients presenting with these factors may benefit from more aggressive and targeted therapies. Furthermore, XGBoost ML model was trained using the dataset of 3324 patients, which was divided into an 80 % training set and a 20 % test set. The model achieved an impressive accuracy of 95 % on both training and test sets, as evidenced by the area under the curve (AUC) values of 0.95. The model ranked the presence of DCIS, DCIS component (major versus minor), DCIS grade, multiplicity of the tumor, and ER status as the top four variables for predicting HER2/neu status. To validate the performance of the proposed model, blind HER2 status data from an external validation cohort of 100 cases were utilized. Notably, the model demonstrated a sensitivity of 90.5 %, indicating its ability to accurately identify HER2-positive cases, and a specificity of 84.4 %, suggesting its capability to correctly classify HER2-negative cases. These results highlight the promising predictive efficacy of AI-based ML in determining HER2 status in breast cancer patients. The model's ability to accurately identify HER2-positive cases can assist in guiding treatment decisions, ensuring that patients receive appropriate and targeted therapies. However, further research with larger datasets is necessary to validate and generalize these findings.

The human epidermal growth factor receptor 2 (HER2) alterations are significant genetic alterations in non-small cell lung cancer (NSCLC), encompassing mutations, amplifications, and protein overexpression. Despite the substantial progress of anti-HER2 targeted therapies in breast and gastric cancers, numerous challenges persist in the treatment of NSCLC with HER2 alterations. Presently, the options for NSCLC with HER2 alterations remain limited, with inferior efficacy observed using small molecule anti-tumor targeted agents and conventional chemotherapy. Antibody drug conjugates (ADCs), an organic combination of monoclonal antibodies and cytotoxic drugs targeting specific tumor cells, have revolutionized the treatment landscape of NSCLC with HER2 alterations. Extensive exploration of ADCs has been conducted across NSCLC patients with HER2 alterations, achieving notable efficacy in some populations. This review aims to delve into the biological characteristics and current treatment landscape of NSCLC with HER2 alterations, emphasizing the transformative research advancements surrounding ADCs. By highlighting these developments, we aspire to provide essential insights to enhance clinical practice and improve management strategies for NSCLC patients with HER2 alterations.

We have previously demonstrated that GLUT1 can interact with phosphorylated EGFR and has an oncogenic role in lung cancer. Here, we aim to investigate their binding region and its signaling pathways.

The AlphaFold 3 prediction, Co-immunoprecipitation, and Western blot were used to uncover the interaction conditions of GLUT1 and EGFR. The RNA-seq data was analyzed to evaluate the difference in signaling pathways between wild-type EGFR and activated mutated EGFR. The xenograft tumor model was established to determine the therapy effect of the combination of GLUT1 inhibitor BAY-876 and EGFR TKI Osimertinib.

We found that the interaction ability of GLUT1 and EGFR depended on the activation of EGFR. GLUT1 interacted with EGFRvIII (loss 2-7 exons) but not with EGFRvI (loss 1-16 exons), so GLUT1 interacts with EGFR in the EGFR extracellular transmembrane region. GLUT1 regulated EGFR downstream signaling pathways. GLUT1 inhibitor BAY-876 can sensitize tumor cells to EGFR TKI Osimertinib.

GLUT1 participates in tumor progression by interacting with phosphor-EGFR, suggesting that inhibition of the GLUT1-EGFR axis may be a potential therapeutic strategy for lung cancer treatment.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, characterized by dysregulated signaling pathways. Many Sophora compounds exhibit potential anti-NSCLC properties. However, the research status, particularly regarding the underlying mechanisms, remains fragmented.

To review the research status as well as mechanisms of Sophora compounds against NSCLC.

A systematic review was conducted on publications retrieved from PubMed, Web of Science and CNKI. The retrieval keywords are paired in various forms of "Sophora compound name" and "non-small cell lung cancer" (including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma). Only experimental (at cell or animal level) or clinical studies demonstrating therapeutic effects of Sophora compounds were included.

>52 Sophora compounds have demonstrated potential anti-NSCLC effects through various signaling pathways, primarily targeting apoptosis induction, cell cycle arrest, and metastasis suppression. Investigated signaling pathways mainly include apoptosis, PI3K/Akt/mTOR, MAPK, STAT3/NF-κB, and EGFR signaling. The expression of apoptotic caspases, Bcl-2, Bax, Akt, mTOR, PI3K, Erk, Jnk, p38, STAT3 and NF-κB is frequently assayed. Notably, most researches have focused on cell models of A549 and H1299, primarily on aforementioned signaling pathways at the protein level.

Many Sophora compounds, particularly flavonoids, show promise as multi-target agents against NSCLC. However, animal experiments and clinical evidence remain limited, and future studies could prioritize investigations on deeper molecular mechanisms, and on little-explored toxicology.

Altered expression and activation of Epidermal Growth Factor Receptor (EGFR) is implicated in acute and chronic kidney injury. One of the important cellular sources of EGFR is the myeloid compartment, which plays roles in both acute kidney injury and subsequent fibrosis. Here we show in a murine ischemic acute kidney injury (AKI) model that myeloid deletion of EGFR promotes a pro-resolving, anti-inflammatory phenotype and increased efferocytotic capacity in macrophages. This leads to accelerated recovery in response to AKI and inhibited subsequent development of tubulointerstitial fibrosis. We find that selective EGFR deletion in neutrophils also accelerates recovery from ischemic kidney injury and reduces subsequent fibrosis. EGFR activation plays an essential role in increasing the life span of neutrophils in the injured kidney. Deletion of EGFR expression either in all murine myeloid cells or selectively in neutrophils decreases kidney neutrophil Mcl-1 expression and promotes neutrophil apoptosis, which is accompanied by accelerated recovery from organ injury and reduced subsequent fibrosis. These studies thus identify coordinated and complementary roles for EGFR activation in neutrophils and macrophages to exacerbate kidney injury.

EGFR-mutated non-small cell lung cancer (EGFRmut NSCLC) represents a heterogeneous group of tumors with varying clinical outcomes. Resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), is inevitable, with emerging evidence suggesting that concurrent genomic alterations influence treatment efficacy.

This retrospective study analyzed 58 stage IV EGFRmut NSCLC patients treated with osimertinib across four hospitals in Madrid, Spain, between March 2021 and February 2023. Comprehensive genomic profiling was conducted using next-generation sequencing (NGS) to evaluate co-mutations. Kaplan-Meier survival curves and Cox regression were applied to assess progression-free survival (PFS) and overall survival (OS).

A second co-mutation was identified in 44.1 % of patients, with TP53 (70 %) being the most frequent, followed by EGFR (11.5 %), PI3K (11.5 %), and MET amplifications (7.7 %). Patients with co-mutations exhibited significantly worse PFS compared to those with only EGFR mutations (HR: 8.0, 95 % CI: 1.81-35.4; p = 0.001). Specifically, TP53 co-mutations were associated with reduced PFS (HR: 21.6, 95 % CI: 2.77-169; p < 0.001) and a non-statistically significant trend toward worse OS (HR: 3.10, 95 % CI: 0.89-10.8; p = 0.062).

This study highlights the prognostic impact of co-mutations, particularly TP53, in EGFRmut NSCLC treated with osimertinib. These findings underscore the need for novel therapeutic approaches and personalized treatment strategies, especially in subgroups with poor prognoses. Trials such as MARIPOSA and FLAURA-2 provide promising evidence for treatment intensification, but careful patient stratification is essential to balance efficacy and toxicity.

IgA nephropathy (IgAN), also known as Berger's disease, is a prevalent kidney disorder caused by the accumulation of IgA antibodies in the glomerular tissue. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs longer than 200 nucleotides, play crucial roles in regulating various cellular and molecular processes, including translation, chromatin remodeling, and transcriptional efficiency. Research has highlighted the significant impact of lncRNA imbalances on the development and progression of kidney diseases, including IgAN. These molecules influence several key signaling pathways, such as PI3K/AKT/mTOR, PTEN, Notch, JNK, and immune-related pathways, with their dysregulation contributing to IgAN pathogenesis. This review aims to provide a comprehensive analysis of the molecular signaling pathways involving lncRNAs in IgAN, underscoring their potential as biomarkers for screening, diagnosis, and prevention. Furthermore, it explores the therapeutic potential of lncRNAs as precise targets for personalized treatment strategies.

Pinctada fucata is a commercially vital species in global pearl aquaculture, producing high-quality pearls. To investigate the molecular regulatory mechanisms of gonadal development in P. fucata, transcriptome analysis was employed to compare expression profiles between testis and ovary across four key developmental stages. A total of 56.86 Gb of clean data was generated, including 392,510 circular consensus sequencing reads, among which 292,295 full-length non-chimeric (FLNC) sequences were identified. A transcript clustering analysis of FLNC reads revealed 89,645 high-quality consensus sequences. 17,646 gene loci were identified, including 8588 novel loci and 28,121 newly discovered transcripts, of which 17,350 were successfully annotated. The boundaries of 12,040 genes on the chromosomes were corrected, and 10,761 complete open reading frame sequences. 281 genes related to gonadal development were identified, including 186 genes with full-length cDNAs in the PacBio library. The study found that HUS1-like, MAD2A-X1, and BLM were stage-specifically upregulated during ovarian maturation, ensuring the accuracy of meiosis. Meanwhile, NR0B1, ETV7L-X5, and CAPRIN1-X2 promoted testicular maturation by regulating somatic cell differentiation and the germ cell microenvironment. KEGG enrichment analysis identified key pathways involved in gonadal development, including the ribosome, oxidative phosphorylation, DNA replication, and lysosome. Fatty acid metabolism was linked to ovarian maturation, while the FoxO and ErbB signaling pathways were associated with testicular maturation. These findings offer valuable insights into the molecular mechanisms regulating gonadal development in P. fucata and enhance genomic resources for this economically important species.

Trichiosanthis Pericarpium (TP) is the dried ripe peel of Trichosanthes kirilowii Maxim., also known as gualoupi in Chinese, effectively clears heat and transforms phlegm. Traditional Chinese medicine (TCM) prescriptions that contain TP are widely used in clinical practice to treat respiratory diseases, including chronic obstructive pulmonary disease (COPD). However, the active ingredients of TP and the potential targets and mechanisms of action of TP against COPD have not been sufficiently investigated.

This study aimed to determine the active ingredients of TP and the potential targets and mechanisms of action of TP against COPD.

The initial phase comprised the screening of potential active ingredients in TP, this was followed by the evaluation of their pharmacodynamic effects through both in vivo and in vitro experiments. Subsequently, network pharmacology and molecular docking were utilized to predict the key targets and associated pathways, which were later validated through animal-related experiments. Finally, the pharmacodynamic basis of TP interacting with the relevant target was identified using surface plasmon resonance (SPR).

The potential active ingredients of TP were predicted by serum chemical composition analysis. The pharmacodynamic effect of Total Flavonoids of Trichiosanthis Pericarpium (TPTF) against COPD was demonstrated by in vivo and in vitro experiments. The targets and pathways of TPTF for COPD were predicted using network pharmacology and confirmed preliminarily by molecular docking techniques. The critical targets and pathways of TPTF against COPD were validated by Western blot and SPR. The active ingredients of TPTF were selected and identified through SPR.

The main active ingredients of TP are flavonoids, which are evaluated through serum chemical composition analysis. TPTF has been demonstrated to be effective in inhibiting inflammation and mucus hypersecretion in both in vivo and in vitro models of COPD. The targets of TPTF against COPD are focused on the EGFR/PI3K/AKT signaling pathway according to Network pharmacology, and the prediction was subsequently validated in the COPD mice. The flavonoids of TP that specifically target on EGFR include Luteolin-7-O-β-d-glucoside, Quercetin-3-O-β-rutinoside, and Apigenin-7-O-glucoside.

This study demonstrates significant progress in understanding how the pharmacodynamic basis and mechanisms of TP improve COPD. The pharmacodynamic ingredients were identified as TPTF through predictions of serum chemical composition, experimental validation, and identification of SPR. The pharmacodynamic mechanisms were also derived from a comprehensive approach that combined network pharmacology, molecular docking predictions, experimental validation, and SPR identification. The innovative integration of different strategies has led to new findings that flavonoid glycosides, such as Luteolin-7-O-β-d-glucoside, Quercetin-3-O-β-rutinoside, and Apigenin-7-O-glucoside in TPTF, enhance the improvement of COPD by reducing inflammation and mucus hypersecretion associated with the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathways.

Cetuximab (Ctx), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) for colorectal cancer treatment, often faces diminished clinical efficacy due to acquired resistance driven by EGFR mutations. Here, we investigated the molecular mechanisms underlying this mutation-induced drug resistance and developed a mechanism-based strategy to restore the binding affinity of Ctx to EGFR mutants. Through molecular dynamics simulations and free energy perturbation calculations, we discovered that most resistant mutations primarily alter the electrostatic properties of the binding interface. Focusing on two key mutations, EGFR K489E and I491M, we rationally designed two Ctx variants-CtxD103R for EGFRK489E and CtxD103E_E105D for EGFRI491M-using electrostatic compensation and steric hindrance adjustment strategies. Surface plasmon resonance measurements verified that the two designed Ctx variants exhibit improved binding affinity to the corresponding EGFR mutants compared with wild-type Ctx. Additionally, western blot experiments using HEK-293T cells showed that the designed CtxD103R effectively inhibits EGF-stimulated phosphorylation of EGFRK489E. Our findings highlight a rational design approach, empowered by interaction landscape at atomic detail, as a promising and cost-effective strategy to combat mutation-driven resistance in antibody therapies.

Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.

Understanding the mechanisms through which anticancer drugs interact with multiple protein targets is crucial for optimizing drug design and enhancing the efficacy of chemotherapy. This study focuses on doxorubicin, a broad-spectrum anticancer drug recognized for its multi-target mechanisms of action. We initially screened 363 doxorubicin-binding proteins using protein microarrays; of these, 166 proteins with known PDB (Protein Data Bank) structures were selected for molecular docking to evaluate their binding energies. The binding energy distribution and residue enrichment analyses revealed that doxorubicin preferentially binds to specific residues at its binding sites, including serine, glycine, arginine, glutamic acid, lysine, aspartic acid, and leucine. These residues stabilize doxorubicin binding through hydrogen bonds, hydrophobic interactions, and electrostatic interactions. In addition, RUVBL1 (RuvB-like AAA ATPase 1) exhibited the highest integrated score from the protein microarray and molecular docking analyses. Furthermore, PPI (protein-protein interaction) network analysis and centrality calculations identified key proteins with potential regulatory roles, with MAPK1 (mitogen-activated protein kinase 1) exhibiting the highest betweenness centrality in the PPI network. Finally, molecular dynamics simulations of the RUVBL1- and MAPK1-doxorubicin complexes were conducted to evaluate the binding mechanisms. The simulations revealed key binding residues, including Ile56, Lys59, Leu87, Pro296, and Ile326 in RUVBL1 and Asp88, Ile89, Pro93, Phe354, and Ala92 in MAPK1 that mediate stable interactions with doxorubicin. This study presents a comprehensive analytical approach for investigating the interactions between doxorubicin and multiple protein targets, providing a reference framework for understanding the molecular mechanisms of anticancer drugs and for future analyses of similar data sets.

The expression of PD-L1 on cancer cells facilitates tumor immune escape by binding to PD-1 on T cells, thereby inhibiting T cell activity. However, the role of intracellular PD-L1 signaling in tumor progression remains unclear. In this study, we demonstrate that CK2 induces PD-L1 phosphorylation at Thr-285, which enhances PD-L1 protein stability. This phosphorylation disrupts the interaction between LC3B and PD-L1, inhibiting PD-L1 degradation via autophagy. Furthermore, PD-L1-T285 phosphorylation promotes EGFR binding to PD-L1, leading to activation of EGFR downstream signaling. This activation drives non-small cell lung cancer (NSCLC) cell proliferation, migration, invasion, and tumor growth. Conversely, CK2 depletion or treatment with a CK2 inhibitor reversed these effects. Our findings reveal a novel mechanism by which the CK2/PD-L1/EGFR pathway promotes tumor progression.

Chimeric antigen receptor-engineered NK cells hold promise for adoptive cancer immunotherapy. In one such approach, the ErbB2 (HER2)-specific CAR-NK cell line NK-92/5.28.z is under investigation as an off-the-shelf therapy in a phase I trial in glioblastoma patients. To evaluate activity of NK-92/5.28.z cells against ErbB2-positive breast cancer, here we developed an organoid model derived from CKP mice that allows conditional activation of oncogenic driver mutations. Expression of ErbB2 and Cre recombinase in CKP mammary epithelial cells induced malignant transformation, with the resulting EC-CKP cells characterized by neoplastic morphology, loss of p53, and constitutive activation of the MAP kinase pathway. NK-92/5.28.z cells demonstrated potent CAR-mediated cytotoxicity against EC-CKP organoids, with tumor cell lysis dependent on exposure time and organoid size. In vivo passaging of EC-CKP organoids revealed cellular plasticity and induced an EMT phenotype associated with increased resistance to standard therapies. Importantly, NK-92/5.28.z cells retained high and specific cytotoxicity against these breast cancer cells in vitro and in an aggressive organoid-based in vivo mouse model that reflects advanced-stage disease. Our data highlight the therapeutic potential of NK-92/5.28.z cells against ErbB2-positive breast cancer, supporting their further development toward clinical application.

Epidermal Growth Factor (EGF) is a multifunctional cytokine that plays an important role in the growth and development of skeletal muscle. In this study, a mouse skeletal muscle post-injury regeneration model and the C2C12 myoblasts cell line were used to elucidate the molecular mechanism by which EGF promotes myoblast proliferation and differentiation and then improves skeletal muscle post-injury regeneration. EGF regulates the activities of p38-MAPK and PI3K/AKT/mTOR signaling pathways through the Epidermal Growth Factor Receptor (EGFR), thereby promoting the proliferation and differentiation of myoblasts. This finding will support the treatment of skeletal muscle injury, which is of great value in resolving muscle health problems such as muscular atrophy and sarcopenia.

The epidermal growth factor receptor (EGFR) family, comprising receptor tyrosine kinases (RTK) such as EGFR and HER2, plays a critical role in various signaling pathways related to cell proliferation, differentiation, and growth. EGFR overactivation due to aberrant signaling can lead to various cancers, including non-small cell lung cancer (NSCLC). To develop treatment for EGFR-related NSCLC, several tyrosine kinase inhibitors (TKIs) were designed: gefitinib, erlotinib, as first-generation; neratinib, dacomitinib as second-generation; osimertinib, lazertinib as third-generation, as examples. However, due to the acquired resistance by the mutations such as EGFRT790M and EGFRC797S together with the exon 20 insertion mutations, these drugs do not provide promising results for NSCLC patients. The development of fourth-generation inhibitors like EAI045 and further innovative drugs to overcome this resistance problem is a must to cure EGFR-related NSCLC. Among these, pyrazoline-thiazole scaffolds are found effective as EGFR-HER2 inhibitors against NSCLC, making them promising drug candidates. Although structures obtained so far for the EGFR family provide meaningful insights into the mechanisms, the quality and the quantity of the EGFR family structures are insufficient to elucidate the complete structures and functions to overcome NSCLC. This review evaluates the structures of EGFR-HER2 and investigates their relation to NSCLC.

Next-generation sequencing has revolutionized genome science over the last two decades. Indeed, the wealth of sequence information on our genome has deepened our understanding on cancer. Cancer is a genetic disease caused by genetic or epigenetic alternations that affect the expression of genes that control cell functions, particularly cell growth and division. Utilization of next-generation sequencing in cancer gene panels has enabled the identification of actionable gene alterations in cancer patients to guide personalized precision medicine.

The aim is to provide information that can identify actionable gene alterations, enabling personalized precision medicine for cancer patients.

Equipped with next-generation sequencing techniques, international collaboration programs on cancer genomics have identified numerous mutations, gene fusions, microsatellite variations, copy number variations, and epigenetics changes that promote the transformation of normal cells into tumors. Cancer classification has traditionally been based on cell type or tissue-of-origin and the morphological characteristics of the cancer. However, interactive genomic analyses have currently reclassified cancers based on systemic molecular-based taxonomy. Although all cancer-causing genes and mechanisms have yet to be completely understood or identified, personalized or precision medicine is now currently possible for some forms of cancer. Unlike the "one-size-fits-all" approach of traditional medicine, precision medicine allows for customized or personalized treatment based on genomic information.

Despite the availability of numerous cancer gene panels, technological innovation in genomics and expansion of knowledge on the cancer genome will allow precision oncology to manage even more types of cancers.

Tumor cells exploit epidermal growth factor receptor (EGFR) family to develop resistance against therapeutic antibodies, such as Herceptin. Upon ligand binding, dimerization between EGFR and HER2 is one of the most important causes of treatment failure in breast cancer and other cancers expressing EGFR and HER2. The aim of this study was to develop and evaluate the function of a human recombinant single-chain variable fragment (scFv) antibody against the dimerization domain of EGFR to inhibit its interaction with other members of the epidermal growth factor receptor family, especially HER2.

scFv against EGFR was expressed and purified. Cell-ELISA, MTT assay, inhibition of STAT3 phosphorylation, quantitative RT-PCR, and dimerization inhibition were performed on EGFR and HER2 expressing cell lines to characterize functional properties of the produced scFv. The conformational structure of the produced scFv and its binding ability to EGFR was computationally investigated.

In vitro binding analysis by cell-ELISA revealed the EGFR binding ability of the purified antibodies and confirmed by immunoblotting. ScFvs preferentially reduced the proliferation and survival of MCF7, MDA-MB-468, and SKOV3 cell lines with no effect on the VERO line. More considerably, MCF7 cells treated with the scFv antibody showed reduced STAT3 phosphorylation, decreased Bcl-2 expression, and increased Bax expression. Finally, the scFvs hindered EGFR and HER2 dimerization.

The produced scFv antibody showed to be functional in a simultaneous blockade of EGFR and HER2, suggesting its potential as a promising candidate for targeted therapy against various EGFR overexpressing tumors.

There is a need for unified guidance in the management of acneiform rash induced by epidermal growth factor receptor inhibitors (EGFRi) among dermatologists.

To establish unified international guidelines for the management of acneiform rash caused by EGFR inhibitors, based on an experts' Delphi consensus.

The initiative was led by five members of the European Academy of Dermatology and Venereology Task Force 'Dermatology for Cancer Patients' who developed a questionnaire that was circulated to a group of 32 supportive oncodermatology experts in Europe, Canada, Argentina, the US States and Asia. The questionnaire consisted of 84 statements in total, regarding diagnosis and treatment of EGFRi-induced acneiform rash. Experts responded to an anonymous 5-point Likert scale survey. The coordinators collected the first-round responses that were checked for consensus (≥75% agreement in positive [agree or strongly agree] or in negative [disagree or strongly disagree] vote). The statements that did not reach strong consensus in the first round were revised, according to experts' feedback, for a second-round survey.

Strong consensus was reached in 75/84 (89.3%) of the statements, whilst moderate consensus was achieved in 6/84 elements. Key points include consideration of low-dose isotretinoin for refractory grade II/III acneiform rash, use of topical steroid-sparing agents like topical pimecrolimus in the maintenance phase and use of doxycycline in either 100 or 200 mg per day as prophylactic treatment. Interestingly, experts did not recommend topical antibiotics, neither for prevention, nor for treatment. Consensus failure in 3/84 objects is mostly related to the lack of robust data on these topics.

This consensus offers crucial insights often overlooked by radiotherapists, general practitioners, dermatologists and oncologists, and it is expected to improve the management of oncologic patients treated with EGFRi in different settings and continents.

Multigene sequencing technologies provide a foundation for targeted therapy and precision oncology by identifying actionable alterations and enabling the development of treatments that substantially improve clinical outcomes. This review emphasizes the importance of having a molecular compass guiding treatment decision-making through the multitude of alterations and genetic mutations, showcasing why NGS plays a pivotal role in modern oncology.

The anti-HER2 monoclonal antibody trastuzumab and new derivative formulations are the standard treatment for HER2-positive breast cancer. However, after 1 to 5 years of treatment, some patients acquire resistance to therapy, leading to relapse. The microRNA-449 family members were downregulated in HER2-positive breast cancer cell lines and low levels were associated with patients' worse prognosis. Moreover, trastuzumab-resistant HER2-positive breast cancer cell lines showed lower microRNAs-449 and higher Fatty Acid Synthase (FASN) expression, compared to sensitive cell lines. The direct regulation of FASN by microRNA-449a and microRNA-449b-5p was demonstrated. Moreover, microRNAs-449 overexpression and FASN inhibition decreased cell proliferation and sensitized cells to trastuzumab treatment by inhibiting the PI3K/AKT signaling pathway. Together, these results suggest the microRNAs-449/FASN axis as a potential therapeutic target in combination with anti-HER2 agents to overcome trastuzumab resistance and to improve treatment response in HER2-positive breast cancer patients.

Non-small-cell lung cancer (NSCLC) represents the most common type of lung cancer. The majority of patients with lung cancer characterized by activating mutations in the epidermal growth factor receptor (EGFR), benefit from therapies entailing tyrosine kinase inhibitors (TKIs). In this regard, osimertinib, a third-generation EGFR TKI, has greatly improved the outcome for patients with EGFR-mutated lung cancer. The AURA and FLAURA trials displayed the superiority of the third-generation TKI in both first- and second-line settings, making it the drug of choice for treating patients with EGFR-mutated lung cancer. Unfortunately, the onset of resistance is almost inevitable. On-target mechanisms of resistance include new mutations (e.g., C797S) in the kinase domain of EGFR, while among the off-target mechanisms, amplification of MET or HER2, mutations in downstream signaling molecules, oncogenic fusions, and phenotypic changes (e.g., EMT) have been described. This review focuses on the strategies that are currently being investigated, in preclinical and clinical settings, to overcome resistance to osimertinib, including the use of fourth-generation TKIs, PROTACs, bispecific antibodies, and ADCs, as monotherapy and as part of combination therapies.

Hepatocellular carcinoma (HCC), the most formidable subtype of primary liver cancers, is becoming increasingly concerning due to its rising incidence worldwide. HCC ranks as the sixth most diagnosed cancer globally and is the third leading cause of cancer-related deaths. Glycosylation, a common post-translational modification of proteins, is frequently altered in tumors and is associated with the progression of malignancies. GALNT1 and GALNT2 are GalNAc-transferases that initiate protein O-glycosylation and are closely linked to cancer development. Investigating the relationship between GALNT1 and GALNT2 in HCC could provide new insights into the disease's pathogenesis. Thus, this study aimed to explore the combined effects of GALNT1 and GALNT2 transfection on HCC, compared to the effects of modifying each gene individually.

GALNT1 and GALNT2 were assessed by bioinformatics, qPCR, and Western blot analyses to detect their expression in HCC tissues and cell lines. The effects of GALNT1/GALNT2 overexpression and knockdown on cell viability, proliferation, migration, invasion, and apoptosis were evaluated in HCC cells using CCK8, colony formation, transwell migration and invasion, wound healing, TUNEL, and flow cytometry assays. EGFR protein levels were also analyzed by Western blotting.

Co-transfection of GALNT1 knockdown with GALNT2 overexpression significantly suppressed proliferation, migration, and invasion, while promoting apoptosis in HCC cells. Conversely, co-transfection of GALNT1 overexpression with GALNT2 knockdown enhanced these malignant characteristics compared to the modified single gene. Notably, we observed that GALNT1 and GALNT2 modulated EGFR protein expression. Overall, our findings suggest that the combined activity of GALNT1 and GALNT2 is critical in regulating HCC malignant behaviors.

Gastric cancer (GC) ranks as the fifth most prevalent cancer on a global scale, with HER2-positive GC representing a distinct subtype that exhibits more intricate biological characteristics. Conventional chemotherapy typically exhibits restricted efficacy in the management of HER2-positive GC. In light of the incessant advancement in molecular targeted therapies, targeting HER2 has emerged as a promising therapeutic approach for this subtype. The advent of antibody-drug conjugates (ADCs) and chimeric antigen receptor T-cell therapy (CAR-T) has furnished novel treatment alternatives for HER2-positive GC. Nevertheless, owing to the pronounced heterogeneity of GC and the complex tumor microenvironment, drug resistance frequently emerges, thereby substantially influencing the effectiveness of HER2-targeted therapy. This article comprehensively summarizes and deliberates upon the strategies of HER2-targeted therapy as well as the underlying resistance mechanisms.

Skin fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) in the dermis, can lead to hypertrophic scars and impaired mobility. The ErbB family of receptor tyrosine kinases, including ErbB1 and ErbB2, plays a crucial role in organ fibrosis, but their specific impact on skin fibrosis is less understood. This study investigated the role of ErbB1 and ErbB2 in skin fibrosis and the therapeutic potential of lapatinib, a dual ErbB1 and ErbB2 tyrosine kinase inhibitor. Using qPCR, cell culture assays, Western blotting, and in vivo models, we found significant upregulation of ErbB1 and ErbB2 in keloid tissues and fibroblasts. Lapatinib treatment resulted in a dose-dependent decrease in ErbB1 and ErbB2 expression, which suppressed the expression of fibroblast activation markers. Our findings suggest that lapatinib may be a promising therapeutic agent for skin fibrosis by targeting ErbB1/ErbB2 and modulating the TGF-β1/Smad2/3/Erk/Akt signalling pathways. These results warrant further clinical investigation into lapatinib for treating skin fibrosis and related conditions.

The predictive and prognostic role of HER2 status in patients with luminal-HER2 negative early breast cancer (BC) undergoing neoadjuvant chemotherapy is unclear. A retrospective analysis evaluating the correlation between HER2 status (low vs. score 0) and pCR/IDFS was conducted.

Patients with BC undergoing neoadjuvant chemotherapy and surgery were included. HER2 low BC was defined as IHC 1+ or 2+ with negative FISH. Logistic regression model and Cox proportional hazard model were adopted to investigate the independent role of HER2 status and outcomes of interest (pCR, CPS-EG and IDFS).

About 566 patients were included: 60% were HER2 low and 40% were HER2 0. pCR was achieved in 13.2% of HER2 low versus 17.7% of HER2 0 (P = .15). There was no correlation between baseline HER2 status and CPS-EG score (P = .18). A trend toward improved IDFS for HER2 low BC was observed (P = .07). The relapse rate of the HER2 0 cohort peaked at 12 months after surgery, similar to the HER2 low cohort, which showed an additional peak at 36 months after surgery.

Among Luminal-HER2 negative early BCs, our results do not support a clear predictive and prognostic effect of HER2 status, although a trend of worse pCR and better survival for HER2 low BCs cannot be ruled out.

The pseudokinase HER3 emerges as a promising anti-cancer target, especially for HER2-driven breast cancer and EGFR-mediated non-small cell lung cancer. However, it is challenging to target HER3 by ATP-competitive small molecules because HER3 is catalytically impaired. Herein, we report the discovery of a series of HER3 degraders by connecting a HER3 binder bosutinib with a hydrophobic tag adamantane. The optimal compound CZY43 effectively induced HER3 degradation in dose- and time-dependent manners in breast cancer SKBR3 cells. Mechanistic studies revealed compound CZY43 to induce HER3 degradation via autophagy. Importantly, compound CZY43 potently inhibited HER3-dependent signaling, cancer cell growth and cell adhesion, and was more potent than bosutinib. This study further suggested that HER3 can be modulated by small-molecule degraders, and compound CZY43 can serve as a lead compound for further optimization.

Amphiregulin (Areg), a growth factor produced by regulatory T (Treg) cells to facilitate tissue repair, contains a heparan sulfate (HS) binding domain. How HS, a highly sulfated glycan subtype that alters growth factor signaling, influences Areg repair functions is unclear. Here we report that inhibition of HS in various cell lines and primary lung mesenchymal cells (LMC) qualitatively alters Areg downstream signaling. Utilization of a panel of cell lines with targeted deletions in HS synthesis-related genes identifies the glypican family of HS proteoglycans as critical for Areg signaling. In the context of influenza A virus (IAV) infection in vivo, an Areg-responsive subset of reparative LMC upregulate glypican-4 and HS; conditional deletion of HS primarily within this LMC subset results in reduced repair characteristics following IAV infection. This study demonstrates that HS on a specific lung mesenchymal population is a mediator of Treg cell-derived Areg reparative signaling.