Abstract 2412: Emergence of resistance to MTI-101 selects for favorable MET phenotype in lung cancer

Abstract

Abstract Lung cancer remains the most-deadly of all cancers, and thus clinical evidence indicates novel treatment strategies are needed to improve patient outcomes. Our laboratory has been developing a novel cyclic peptide coined MTI-101, which induces cell death via calcium overload, a finding dependent on the TRPC1/TRPC5/TRPC4 complex. To better understand determinants of sensitivity and resistance to MTI-101, we developed drug resistant isogenic lung cancer cell lines. Two isogenic drug resistant cell lines were generated with chronic exposure to MTI-101 in PC-9 (NSCLC EGFR Driven) and H446 (SCLC PTEN Deleted and c-MYC amplified). Drug resistance was confirmed in both cell lines with over two-fold increases in IC50 values upon treatment with MTI-101 in MTT assays. Interestingly, pushing the resistant levels beyond a two-fold increase was not obtained as cultures did not sustain growth with increased selection pressure. Using the isogenic systems coupled with RNA-SEQ, the top enriched GSEA hallmark was downregulation of genes that contribute to EMT in both MTI-101 resistant lines. The RNA-SEQ data correlated with changes in the phenotype which included a significant decreased invasion in Matrigel and changes of MET markers (E-Cadherin, Vimentin) at the protein level. Furthermore, in the EGFR driven PC-9 cell line, selection for resistance towards MTI-101 resulted in collateral sensitivity to EGFR inhibitors. To determine the stability of the MET phenotype, cells were removed from drug, then tested for invasion and drug resistance every month. Our data indicated that the MET phenotype and genotype was stable for a minimum of six months. RNA-SEQ data continued to demonstrate decreased expression of EMT in cells removed from drug compared to the parental cell line. MTI-101 treatment in PC-9 and H446 cells showed synergistic activity with standard of cares Erlotinib, Osimertinib, and Cisplatin when used in combination on the wildtype cells as well. Finally, in vivo data indicates that MTI-101 treatment selects for increased E-Cadherin and decreased Vimentin. Similar to the cell line model, this finding correlated with decreased incidence of bone metastasis in the PC-9 in vivo model. Together our data indicate that MTI-101 treatment could be used as a tool to delay the emergence of resistance and potentially inhibit or delay the emergence of metastatic disease for the treatment of lung cancer. Citation Format: Clark Jones, Lori Hazlehurst. Emergence of resistance to MTI-101 selects for favorable MET phenotype in lung cancer [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 2412.