Abstract 207: MET inhibition enhances the effect of radiation in MET mutated non-small cell lung cancer brain metastasis patient derived xenografts

Abstract

Abstract Objective: The MET receptor is mutated in 3-4% and amplified in 1-6% of patients with non-small cell lung cancer. The most common MET mutation is in exon 14, which results in deletion of the intracellular juxtamembrane domain of the receptor, leading to enhanced signaling. Mutation at Asp-1000 in the juxtamembrane region has also been reported and can lead to inhibition of apoptosis and cell proliferation. MET is involved in multiple pathways associated with radiation response. Therefore, we investigated the effects of inhibiting MET in combination with radiation in two preclinical non-small cell lung cancer (NSCLC) brain metastasis patient derived xenograft (PDX) models. Methods: Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. Histology and DNA loci were compared between original tumor and PDX. DNA sequencing was performed on tumors for mutation analysis. In vivo growth responses to the MET inhibitor capmatinib or savolitinib with and without radiation were assessed. Radiation was delivered in 10 daily fractions of 2 Gy. Drug was administered by oral gavage daily 1 hour prior to radiation at a dose of 2.5 mg/kg for savaolitnib or 20 mg/kg for capmatinib for 10 days. Immunohistochemistry (IHC) was performed to evaluate MET signaling and proliferation. Results: PDXs were successfully established from two patients with MET mutated NSCLC brain metastases: a lung adenocarcinoma with a MET exon 14 skipping mutation and a lung sarcomatoid carcinoma with adenocarcinoma component with an Asp-1000 frameshift mutation. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Short tandem repeat analysis confirmed 100% matching of alleles between patient tumors and PDXs. DNA sequencing confirmed METex14 and MET Asp-1000 frameshift mutation. In the METex14 PDX, savolitinib alone significantly inhibited tumor growth with a growth inhibition value of 46% (p<0.01). Combination of savolitinib and radiation significantly delayed growth compared to vehicle control, savolitinib alone or radiation alone (p<0.001). The absolute growth delay was 42.4 days for savolitinib plus radiation treatment compared to 9.3 days for savolitinib alone and 28.2 days for irradiation. In the MET Asp-1000 PDX, capmatinib and radiation significantly delayed growth compared the other treatment arms (p<0.01). IHC demonstrated inhibition of phospho-MET and pS6 and a decrease in Ki67 with MET inhibition. Conclusion: Inhibition of MET enhanced the effect of radiation in our two preclinical in vivo MET mutated NSCLC brain metastasis models. Additional studies are currently underway evaluating the mechanisms of radiation sensitization and the efficacy of this combination in MET amplified PDX models. Citation Format: Kwangok P. Nickel, Shrey Ramesh, Saahil Javeri, Nitin Somasundaram, Nan Sethakorn, Randall J. Kimple, Andrew M. Baschnagel. MET inhibition enhances the effect of radiation in MET mutated non-small cell lung cancer brain metastasis patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 207.