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

Sep 21, 2026

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Lung cancer causes a high burden of cancer-related mortality worldwide, and lung adenocarcinoma (LUAD) frequently carries activating KRAS mutations linked to poor prognosis and limited therapeutic options. Intrinsic or acquired resistance reduces the long-term efficacy of KRASG12C inhibitors such as sotorasib. This study identifies FBXL16 as selectively upregulated in KRAS-mutant LUAD and shows that FBXL16 depletion markedly increases sensitivity to KRASG12C inhibition in resistant cells. Mechanistically, FBXL16 enhances IRS1 protein stability, elevating IGF1/AKT signaling to drive LUAD cell growth and migration, supporting FBXL16 as a potential therapeutic target.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Background on LUAD and KRASG12C resistance

Rationale for targeting FBXL16 in NSCLC/LUAD

Study focus and proposed mechanism

Abbreviations

FBXL16 promotes cell growth and drug resistance in lung adenocarcinomas with KRAS mutation by stabilizing IRS1 and upregulating IRS1/AKT signaling Marion Morel and Weiwen Long Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA Keywords AKT; FBXL16; IRS1; KRAS; lung adenocarcinoma; protein stability Correspondence W. Long, Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH 45435, USA Tel: +1 (937)775-3172 [E-mail:](E-mail: weiwen.long@wright.edu)[ weiwen.long@wright.edu](E-mail: weiwen.long@wright.edu) (Received 18 July 2023, revised 17 October 2023, accepted 15 November 2023, available online 17 January 2024) doi:10 . 1002/1878-0261 .13554 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 KRASG12Chas 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. 1. Introduction With 1.8 million deaths in 2020, lung cancer is the leading cause of cancer death worldwide [1] . Accounting for 85% of the cases, non-small-cell lung cancer (NSCLC) is the most common type and is categorized into different subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) . LUAD is the most prevalent subtype (around 40%) of NSCLCs and is commonly associated with genetic mutations. Mutation in the Kirsten rat sarcoma (KRAS) gene occurs in about 25% of LUAD cases and is implicated in tumor aggressiveness and poor prognosis [2,3] . Recently, novel covalent inhibitors speciﬁcally targeting KRASG12C, such as sotorasib (AMG-510) and adagrasib (MRTX-849), have demonstrated encouraging clinical response. However, rapid development of either intrinsic or acquired resistance limits its long-term efﬁcacy [4–8] . Thus, it becomes crucial to identify new therapeutic targets and elucidate the underlying mechanisms associated with resistance to improve treatment outcomes. FBXL16 is an F-box protein harboring an N-terminal proline-rich domain, an F-box motif, and a C-terminal Abbreviations CHX, cycloheximide; CUL1, cullin1; ERK, extracellular signal regulated kinase; IGF1, insulin growth factor 1; IRS1, insulin receptor substrate 1; KRAS, Kirsten rat sarcoma; LRR, leucine-rich repeat; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NSCLC, nonsmall-cell lung cancers; OS, overall survival; PI3K, phosphoinositide 3-kinases; S6K, ribosomal protein S6 kinase; SKP1, S-phase kinase associated protein 1; SRC3, steroid receptor coactivator 3; TMA, tissue microarray. 762 Molecular Oncology 18 (2024) 762–777 ª 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behal

FAQs

What role does FBXL16 play in KRAS-mutant lung adenocarcinoma?

FBXL16 is selectively upregulated in LUAD with KRAS mutations and promotes LUAD cell growth while transforming lung epithelial cells.

How does FBXL16 affect response to KRASG12C inhibitors like sotorasib?

Depleting FBXL16 greatly enhances sensitivity to KRASG12C inhibition in resistant cells by downregulating PI3K/AKT signaling.

What mechanism connects FBXL16 to AKT signaling?

FBXL16 upregulates insulin receptor substrate 1 (IRS1) protein stability, which increases IGF1/AKT signaling and thereby promotes growth and migration.

Sep 21, 2026

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