FBXL16 promotes cell growth and drug resistance in lung adenocarcinomas with KRAS mutation by stabilizing IRS1 and upregulating IRS1/AKT signaling

Abstract

Lung cancer is the leading cause of cancer‐related deaths worldwide. Lung adenocarcinomas (LUADs) are a major subtype of non‐small‐cell lung cancers (NSCLCs). About 25% of LUADs harbor GTPase KRAS mutations associated with poor prognosis and limited treatment options. While encouraging tumor response to novel covalent inhibitors specifically targeting KRASG12C has been shown in the clinic, either intrinsic resistance exists or acquired therapeutic resistance arises upon treatment. There is an unmet need to identify new therapeutic targets for treating LUADs with activating KRAS mutations, particularly those with resistance to KRASG12C inhibitor(s). In this study, we have revealed that F‐box/LRR‐repeat protein 16 (FBXL16) is selectively upregulated in LUAD with KRAS mutations. It promotes LUAD cell growth and transforms lung epithelial cells. Importantly, FBXL16 depletion greatly enhances sensitivity to the KRASG12C inhibitor (sotorasib) in resistant cells by downregulating phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB; also known as AKT) signaling. Mechanistically, FBXL16 upregulates insulin receptor substrate 1 (IRS1) protein stability, leading to an increase of IGF1/AKT signaling, thereby promoting cell growth and migration. Taken together, our study highlights the potential of FBXL16 as a therapeutic target for treating LUAD with KRAS activating mutations.