Lung cancer and gastric cancer remain two of the most formidable challenges in oncology worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and continues to be the leading cause of cancer-related mortality globally. Gastric cancer ranks as the fifth most common cancer worldwide and the fourth most lethal in terms of cancer-related deaths. Despite gradual improvements in early detection and treatment modalities, outcomes for patients with advanced-stage disease remain poor, driving an urgent need for novel therapeutic strategies.

The treatment landscape for both malignancies has been fundamentally transformed by the advent of biomarker-driven precision medicine. In gastric cancer, therapies are now guided by key biomarkers such as HER2, PD-L1, dMMR/MSI-H, and most recently CLDN18.2, while FGFR2b is emerging as a promising new target in this field. In NSCLC, immune checkpoint inhibitors targeting the PD-1/PD-L1 and CTLA-4 axes have revolutionized treatment, yet primary resistance affects 5–20% of patients and acquired resistance remains a major clinical obstacle. This review synthesizes recent advances in understanding key molecular targets—c-MET, FGFR2, EZH2, CK2, and Nectin-4—that are reshaping the therapeutic paradigm for lung and gastric cancers.

The c-MET Signaling Pathway: A Critical Driver in NSCLC and Gastric Cancer

The c-Met receptor tyrosine kinase, upon activation by its ligand hepatocyte growth factor (HGF), plays an essential role in regulating cellular processes including proliferation, survival, and metastasis. Dysregulation of c-Met signaling—through overexpression, gene amplification, or mutations—is associated with the development and progression of various cancers, including NSCLC, gastric cancer, and hepatocellular carcinoma.

MET gene amplification represents a common oncogenic mechanism in gastric cancer and constitutes an attractive therapeutic target.The clinical translation of c-Met-targeted therapies has been facilitated by significant advancements in molecular diagnostics, enabling precise identification of patients eligible for such treatments. However, the emergence of resistance—driven by secondary mutations, activation of alternative signaling pathways, and tumor cell phenotypic changes—remains a major hurdle. Current therapeutic approaches targeting c-Met include small molecule inhibitors, monoclonal antibodies, and combination therapies designed to overcome resistance.

FGFR2: An Emerging Biomarker and Therapeutic Target in Gastric Cancer

Fibroblast growth factor receptor 2 (FGFR2) has recently emerged as a promising biomarker and therapeutic target in gastric cancer. The FGFR2b isoform, in particular, is under phase 3 clinical investigation for gastric and gastroesophageal junction adenocarcinoma with the novel monoclonal antibody bemarituzumab.

FGFR2 overexpression is detected through various methods including immunohistochemistry and fluorescence in situ hybridization, though intra-tumoral heterogeneity of FGFR2 expression presents challenges for clinical implementation. The biological functions of FGFR2 in gastric cancer are multifaceted: it promotes tumor cell proliferation, survival, and invasion through activation of downstream signaling cascades including the MAPK and PI3K/AKT pathways.

The therapeutic potential of targeting FGFR2 is substantial. Beyond bemarituzumab, multiple

Epigenetic and Post-Translational Checkpoints: EZH2 and CK2 in Immunotherapy Resistance

The intersection of epigenetics and tumor immunology has revealed new vulnerabilities in lung cancer. Enhancer of zeste homolog 2 (EZH2), a pivotal epigenetic regulator, fosters an immunosuppressive tumor microenvironment and drives immunotherapy resistance. Pharmacological inhibition of EZH2 has emerged as a rational strategy to sensitize tumors to immune checkpoint blockade.

Recent studies demonstrate that the novel EZH2 inhibitor XNW5004 enhances anti-tumor immunity in lung adenocarcinoma through multiple mechanisms. XNW5004 stimulates chemokine-mediated recruitment of dendritic cells and T cells into tumor sites, upregulates antigen presentation molecule MHC class I, and augments the cytotoxic activity of both CD8⁺ T cells and natural killer cells. The STING-TBK1-NF-κB axis functions as a pivotal regulatory signaling pathway driving these phenotype alterations. In preclinical models, the combination of EZH2 inhibition with PD-1 blockade produced synergistic antitumor efficacy, establishing this combinatorial approach as a promising therapeutic strategy.

Nectin-4: A Novel Target for ImmunoPET Imaging and Theranostics

Beyond therapeutic targets, novel biomarkers are enabling advanced diagnostic and imaging strategies. Nectin-4, a cell adhesion molecule overexpressed in multiple solid tumors, has recently been evaluated as a target for immunoPET imaging in both gastric cancer and NSCLC.

The Adaptive Resistance Challenge: AXL-Mediated Escape from HER2-TKIs

The phenomenon of adaptive resistance continues to challenge the durability of targeted therapies. In HER2-aberrant lung and gastric cancers—where HER2 aberrations are observed in approximately 10–20% of gastric cancer and 2–5% of lung cancer cases—HER2 tyrosine kinase inhibitors (TKIs) such as mobocertinib, poziotinib, and tucatinib have shown clinical efficacy. However, achieving complete tumor remission remains challenging.

Recent mechanistic studies have uncovered that the AXL receptor is activated by HER2-TKIs and maintains cell survival through interaction with EGFR, HER2, and HER3. This process, mediated by the SHC1BP–SHC1 axis, contributes to adaptive resistance to HER2-TKIs in a subset of HER2-aberrant lung and gastric cancers. Importantly, AXL inhibition significantly delayed tumor regrowth of AXL-overexpressing cells by enhancing HER2-TKI-induced apoptosis in xenograft models. These findings suggest that patients with HER2-aberrant lung and gastric cancers exhibiting high AXL expression may benefit from an initial combination therapy with an AXL inhibitor.

Conclusion

The therapeutic landscape for lung and gastric cancers is evolving rapidly, driven by the identification of novel biomarkers and the development of targeted therapeutic strategies. From c-MET and FGFR2 as direct oncogenic drivers, to EZH2 and CK2 as epigenetic and post-translational regulators of immune evasion, to Nectin-4 as a diagnostic imaging target, the molecular understanding of these malignancies continues to expand.

To support these research endeavours, BOT Bioscience offers a comprehensive portfolio of high\u001equality monoclonal antibodies, recombinant proteins, and custom conjugation services. Researchers can easily browse and order products targeting c\u001eMET, VEGF, CD73, CD90, CD105, CD171, CD79B, and many other key biomarkers directly via the online catalogue. For custom assay development, bulk orders, or technical consultations, the scientific support team is available to provide tailored solutions.

For researchers working at the forefront of cancer biology and therapeutic development, access to high-quality research reagents—including monoclonal antibodies, recombinant proteins, and custom conjugation services—remains essential for elucidating these complex molecular pathways and accelerating the path from bench to bedside.

[1] Lages Dos Santos J, Caetano Oliveira R, Gama JM. The Role of FGFR2 as a Novel Biomarker for Treatment of Gastric Cancer-A Literature Review. Medicina (Kaunas). 2025 Oct 22;61(11):1890. doi: 10.3390/medicina61111890. PMID: 41303727; PMCID: PMC12654675.

[2] Lages Dos Santos J, Caetano Oliveira R, Gama JM. The Role of FGFR2 as a Novel Biomarker for Treatment of Gastric Cancer-A Literature Review. Medicina (Kaunas). 2025 Oct 22;61(11):1890. doi: 10.3390/medicina61111890. PMID: 41303727; PMCID: PMC12654675.

[3] Ishida, M., Yamada, T., Katayama, Y. et al. AXL–SHC1 signaling axis mediates adaptive resistance to HER2-targeted tyrosine kinase inhibitors in HER2-aberrant lung and gastric cancers. npj Precis. Onc. 10, 142 (2026). https://doi.org/10.1038/s41698-026-01385-2