Abstract 7195: Repurposing non-oncology drugs with MET inhibitory effect to overcome osimertinib resistance in lung cancer

Abstract

Abstract Background and Aim: Osimertinib is the only 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for the 1st line therapy of advanced NSCLC patients with EGFR mutations. However, drug resistance is severely limiting its clinical efficacy. Aberrant MET activation is an important mechanism causing osimertinib resistance. There is no effective therapeutic option after osimertinib failure. This study investigated the repurposing of non-oncology MET inhibiting drug to overcome osimertinib resistance. Method: A few clinically-approved drugs with putative MET inhibitory effects were identified by a computational drug repurposing tool called “DRAR-CPI” via analysis of the chemical-protein interactome of known MET inhibitors (crizotinib, cabozantinib, foretinib, and tivantinib). Fexofenadine (FEX), originally indicated for allergic rhinitis and chronic urticaria, was chosen for detailed investigation in osimertinib-resistant NSCLC cell lines that exhibit aberrant MET activation with/without other EGFR-dependent osimertinib resistance mechanisms. The selectivity of kinase inhibition by FEX was evaluated by a KINOME profiling assay against a panel of human protein kinases. Western blot analysis was conducted to examine the activation status of Met and EGFR downstream signaling. RNA sequencing was performed to identify differentially expressed genes (DEGs) triggered by the most promising repurposed drug, presumably contributing to osimertinib resistance circumvention. Sulforhodamine B assay was used to evaluate cell proliferation. The circumvention of osimertinib resistance by FEX was further verified in a patient-derived tumor xenograft (PDX) from an advanced-stage osimertinib-refractory NSCLC patient. Result: FEX was found to inhibit recombinant MET kinase in cell-free assays in a dose- and time-dependent manner. It also inhibited MET phosphorylation and other downstream signaling molecules in osimertinib-resistant NSCLC cell lines harboring EGFR T790M+MET amplification or EGFR T790M loss+MET amplification. KINOME profiling revealed a similar kinase inhibition profile between FEX and cabozantinib using Spearman rank order correlation analysis. Among the tested osimertinib-resistant NSCLC cell lines, FEX showed the highest effectiveness in potentiating the anticancer effect of osimertinib in H820 cells (having MET amplification & EGFR T790M mutation). Transcriptome profiling analysis in H820 cells before and after FEX treatment revealed that the majority of DEGs were enriched in EMT-related biological processes and pathways. FEX was further shown to significantly potentiate the antitumor effect of osimertinib in a drug refractory PDX model, without inducing notable weight loss in the animals. Conclusion: These findings advocate the clinical evaluation of repurposing FEX to overcome osimertinib resistance. Citation Format: Kenneth K.W. To, Kwong Sak Leung, William C.S. Cho. Repurposing non-oncology drugs with MET inhibitory effect to overcome osimertinib resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7195.