Abstract 109: The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation

Abstract

Abstract F-box proteins are essential components of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligases in that they bind to SKP1 through the F-box motif and bring the substrate to the E3 ligase complex for ubiquitination. FBXL16 is a poorly studied F-box protein. FBXL16 doesn’t interact with Cul1 and might not form a functional SCF-E3 ligase complex. Unexpectedly, we recently found that FBXL16 upregulates several oncoproteins targeted by SCF-E3 ligases, such as SRC-3 and c-myc, by antagonizing the activity of another F-box protein, FBW7. By data mining, we found that FBXL16 is highly upregulated in many cancers, including lung adenocarcinomas (LUADs), and its upregulation is associated with poor overall survival. LUAD is the most common form of lung cancer, and about 30% of LUADs harbor constitutively active oncogenic KRAS mutants. However, currently no drug is available for effectively treating LUADs expressing KRAS mutants. Hence, there is an unmet need to identify new therapeutic targets. Here, we report that FBXL16 protein level is selectively upregulated and is strongly correlated with insulin receptor substrate-1 (IRS1) protein expression in LUAD cell lines with activating KRAS mutations. By cycloheximide treatment, we found that FBXL16 greatly increases IRS-1 protein stability and level, leading to upregulation of IGF-1 (Insulin)/IRS1/PI3K Akt signaling. Importantly, the upregulation of IRS1 protein and its signaling by FBXL16 was confirmed in mouse lungs with conditional overexpression of FBXL16 transgene. Moreover, depletion of FBXL16 by RNA interference inhibits IGF-1-induced lung cancer cell proliferation and migration. Taken together, our findings reveal FBXL16 as a potential target for treating LUADs with KRAS activating mutations. Citation Format: Marion Morel, Weiwen Long. The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation [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 109.