36P - Comparison of pelitinib, tepotinib or docetaxel efficacy according to the copy number or gene alteration status of EGFR, MET, HRAS, KRAS and NRAS genes

Background

In gastric cancer (GC), MET and EGFR amplification have been identified in about 2-24% and 27-64% of GC patients respectively. In this study, we characterized 286 carcinogenesis-related gene alteration and copy number variations (CNVs) in 4 human GC cell line and analyzed difference in the susceptibility of these cells to pelitinib, tepotinib or docetaxel.

Methods

Utilizing next-generation sequencing panel, we evaluated the 286 gene alteration and CNVs in 4 GC cells. Also, we assessed the antitumor activity of pelitinib, tepotinib and docetaxel in GC cell lines and xenograft model. The effect of pelitinib, tepotinib and docetaxel on cell viability (IC₅₀), apoptotic cell death, tumor volume and H&E staining were evaluated by MTS and flow cytometry. Antitumor efficacy was assessed in MKN45 xenograft mice.

Results

Compared to tepotinib, pelitinib inhibited the growth of GC cells with a gained EGFR (CNV > 3, without HRAS, KRAS and NRAS mutation) and amplified MET (CNV > 30) in a dose-dependent manner with a concomitant induction of cell death. In a murine xenograft model, tumor volumes were significantly reduced in the pelitinib, tepotinib or docetaxel-treated groups, when administered by daily oral gavage at a dose of 10, 10, 5 mg/kg/day respectively. Histologically, pelitinib, tepotinib or docetaxel induced more necrosis than in the control group.

Conclusions

We found that pelitinib has anti-tumor activity not only in EGFR gain GCs without mutated HRAS, KRAS and NRAS but also MET amplified GCs.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

This research was funded by the Korea Health Technology R&D Project (grant number HI22C1375) and the National Research and Development Program for Cancer Control (grant number HA17C0054), Ministry of Health and Welfare, and Hallym University Research Fund, which had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Disclosure

All authors have declared no conflicts of interest.