Abstract 5690: Targeting MET activation in CDH1 deficient diffuse gastric cancer with peritoneal metastases

Abstract Background: Peritoneal metastasis (PM) is common in advanced gastric cancer (GC). PM has a poor prognosis with a short average survival of 2 to 9 months. Currently, the only treatment option for these patients is palliative chemotherapy, which has poor efficacy. Improving patient survival requires a better treatment approach. Germline mutations in CDH1 (E-cadherin) tumor suppressor gene are associated with hereditary diffuse gastric cancer (HDGC) syndrome, a very aggressive form of GC and lobular breast cancer. Our prior studies on GC PM patient samples have demonstrated increased incidence of CDH1 deficiency (mutations/deletions; 26%) compared to primary tumor samples (9%). Further molecular integrated analysis has shown that CDH1 mutant tumors are correlated with increased expression of MET oncogene, suggesting that targeting MET could be beneficial in the treatment of the subset of PM patients with CDH1 deficiency (somatic or germline). This study seeks to target MET activation in CDH1 deficient diffuse GC cells. Methods: Three diffuse GC cell lines derived from human PM samples were used: SNU-16 (CDH1 wild-type), GA0518 (CDH1 deletion), and MKN45 (CDH1 mutant). We examined MET and phosphorylated MET (p-MET) expression in all cell lines using qPCR, immuno-blotting and immuno-fluorescence. We then evaluated the in vitro effects of two commercially available MET inhibitors, Cabozantinib and Crizotinib. Drug effects on cell viability, colony formation, migration, and downstream MET signaling pathways were assessed. Results: MET and p-MET expression, and downstream MET signaling were significantly enhanced in CDH1 mutant diffuse GC cell lines compared with the wild-type. Cell viability results demonstrated that CDH1 mutant cell lines were highly sensitive to MET inhibitors. IC50 values showed higher susceptibility for both drugs in CDH1 mutant cell lines, MKN45 (0.01nM and 0.2nM for Crizontinib and Cabozantinib, respectively) and GA0518 (648nM and 824nM) compared to wild-type, SNU16 (1.9uM and 3.2uM). Downstream pathways, PI3K and MAPK, were suppressed at concentrations between 10-50nM. Cell migration and colony formation were inhibited between 10nM-500nM. Conclusions: CDH1 deficient (mutant/deletion) GC cell lines have increased MET expression and activation (p-MET) compared to wild-type cells. We showed that CDH1 mutant cell lines with high MET activation were susceptible to MET inhibitors. Furthermore, at low concentrations, targeting activated MET led to complete loss of p-MET expression, suppression of its downstream signaling, and impaired cell growth, migration, and colony formation. Thus, blockade of MET signaling could be clinically useful for the treatment of CDH1 deficient diffuse GC PM patients, while CDH1 mutations could serve as a biomarker. Future in vivo PDX and syngeneic mouse models are under investigation to validate these results. Citation Format: Hannah Sofield, Hyun-Kyung Ko, Dipti Athavale, Yan-ting Yann Zhan, Xiaodan Yao, Luke Chen, Young K. Hong, Francis Spitz, Generosa Grana, Madeline Torres, Shumei Song. Targeting MET activation in CDH1 deficient diffuse gastric cancer with peritoneal metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5690.