Abstract 2412: MET inhibition enhances the effect of radiation in MET dysregulated non-small cell lung cancer models

Abstract

Abstract Objective: Alterations in the MET receptor are seen in up to 10% of patients with non-small cell lung cancer (NSCLC). A mutation in exon 14, which results in deletion of the intracellular juxtamembrane domain of the receptor, leading to enhanced signaling, is the most common MET mutation in NSCLC. MET is involved in multiple pathways associated with apoptosis and radiation response. We investigated the effects of inhibiting MET with capmatinib, a potent and clinically relevant ATP-competitive kinase inhibitor, in combination with radiation in MET-dependentNSCLC models. Methods: MET exon 14 mutated and MET amplified NSCLC cell lines treated with radiation or capmatinib were assessed with proliferation, clonogenic survival, apoptosis, and DNA damage signaling and repair assays. MET signaling proteins were evaluated by Western blotting. In vivo growth responses to the MET inhibitor capmatinib with and without radiation were evaluated in patient derived xenograft (PDX) models established from both MET amplified and MET exon 14 skipping mutation containing patient tumors. Radiation was delivered in 10 daily fractions of 2 Gy and capmatinib was administered by oral gavage daily 1 hour prior to radiation at a dose 20 mg/kg for capmatinib. Immunohistochemistry (IHC) was performed to evaluate MET signaling and proliferation. Results: Radiation increased the expression and capmatinib inhibited phospho-AKT, phospho-s6,phospho-ERK, and phospho-STAT3 in our MET-driven NSCLC cell lines. Combination of capmatinib and radiation in clonogenic assays increased sensitivity to radiation in MET dysregulated cell lines. No radiation-enhancing effect was observed in MET wild-type and human bronchial epithelial cell lines. Campatinib alone significantly inhibited tumor growth in both ourMET exon 14 mutated and MET amplified xenograft models (p<0.01). Combination of capmatinib and radiation significantly delayed growth compared to vehicle control, capmatinib alone or radiation alone (p<0.01). IHC demonstrated inhibition of phospho-MET and phospho-S6 and a decrease in Ki67 with inhibition of MET. A significant decrease Ki67 proliferation was observed in the combination arm compared to radiation along or drug alone. Conclusion:Inhibition of MET enhanced the effect of radiation in multiple MET-altered NSCLC PDX models.Additional studies are currently underway evaluating the mechanisms of radiation sensitization with a focus on MET-induced apoptosis. Citation Format: Shrey K. Ramesh, Saahil N. Javeri, Kwangok P. Nickel, Ahmet Cifci, Rachel L. Minne, Randall J. Kimple, Andrew M. Baschnagel. MET inhibition enhances the effect of radiation in MET dysregulated non-small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2412.