Epithelial-mesenchymal transition status is a remarkable biomarker for the combination treatment with avutometinib and defactinib in KRAS-mutated non-small cell lung cancer

Abstract

Recent therapeutic strategies that inhibit the MAPK pathway, a key effector pathway in KRAS-mutated cancers, have attracted considerable attention. Among several molecular-targeted drugs, the RAF/MEK clamp avutometinib (VS-6766 /CH5126766/RO5126766/CKI27) is promising for patients with KRASmutated cancers. Although avutometinib monotherapy has shown clinical activity in patients with KRASmutated cancers, effective combination strategies will be important to develop. In this study, we investigated the combination of avutometinib with the focal adhesion kinase (FAK) inhibitor, defactinib, for KRAS-mutated non-small cell lung cancer (NSCLC) cells. Using a phosphorylation kinase array kit, we explored the feedback mechanism of avutometinib in KRAS-mutated NSCLC cells. We further investigated the e cacy of combining avutometinib with inhibitors of the feedback signal using in vitro and in vivo experiments. Moreover, we aimed to identify a biomarker for the e cacy of combination therapy through an in vitro study and analysis using the TCGA dataset. FAK phosphorylation/activation was increased after avutometinib treatment and synergy between avutometinib and defactinib was observed in KRASmutated NSCLC cells with an epithelial rather than mesenchymal phenotype. Combination therapy with avutometinib and defactinib induced apoptosis with upregulation of Bim in cancer cells with an epithelial phenotype. In cell line-derived xenograft models of epithelial phenotype KRAS-mutated NSCLC cells, the combination therapy of avutometinib and defactinib, compared with avutometinib alone, markedly regressed tumors and delayed tumor regrowth after treatment was interrupted. These results demonstrate that the epithelial-mesenchymal transition status may be a promising biomarker for the e cacy of combination therapy with avutometinib and defactinib in KRAS-mutated NSCLC.