FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non–Small Cell Lung Cancer

Author:

Guan Shaoxing1,Chen Xi2,Chen Youhao1,Xie Wen3,Liang Heng1,Zhu Xia1,Yang Yunpeng2,Fang Wenfeng2,Huang Yan2,Zhao Hongyun2,Zhuang Wei1ORCID,Liu Shu1,Huang Min1ORCID,Wang Xueding1,Zhang Li2

Affiliation:

1. 1Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou City, Guangzhou, P. R. China.

2. 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.

3. 3Department of Pharmaceutical Sciences and Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.

Abstract

Abstract Purpose: Although gefitinib prolonged the progression-free survival (PFS) of patients with non–small cell lung cancer (NSCLC), unpredictable resistance limited its clinical efficacy. Novel predictive biomarkers with explicit mechanisms are urgently needed. Experimental Design: A total of 282 patients with NSCLC with gefitinib treatment were randomly assigned in a 7:3 ratio to exploratory (n = 192) and validation (n = 90) cohorts. The candidate polymorphisms were selected with Haploview4.2 in Hapmap and genotyped by a MassARRAY system, and the feature variables were identified through Randomforest Survival analysis. Tanswell and clonogenic assays, base editing and cell-derived tumor xenograft model were performed to uncover the underlying mechanism. Results: We found that the germline missense polymorphism rs3742076 (A>G, S628P), located in transactivation domain of FOXM1, was associated with PFS in exploratory (median PFS: GG vs. GA&AA, 9.20 vs. 13.37 months, P = 0.00039, HR = 2.399) and validation (median PFS: GG vs. GA&AA, 8.13 vs. 13.80 months, P = 0.048, HR = 2.628) cohorts. We elucidated that rs3742076_G conferred resistance to gefitinib by increasing protein stability of FOXM1 and facilitating an aggressive phenotype in vitro and in vivo through activating wnt/β-catenin signaling pathway. Meanwhile, FOXM1 level was highly associated with prognosis in patients with EGFR-mutant NSCLC. Mechanistically, FOXM1 rs3742076_G upregulated wnt/β-catenin activity by directly binding to β-catenin in cytoplasm and promoting transcription of β-catenin in nucleus. Remarkably, inhibition of β-catenin markedly reversed rs3742076_G-induced gefitinib resistance and aggressive phenotypes. Conclusions: These findings characterized rs3742076_G as a gain-of-function polymorphism in mediating gefitinib resistance and tumor aggressiveness, and highlighted the variant as a predictive biomarker in guiding gefitinib treatment.

Funder

National Natural Science Foundation of China

National Key Research and Development Program

Guangdong Provincial Key Laboratory of Construction Foundation

Science and Technology Program of Guangzhou

National Engineering and Technology Research Center for New drug Druggability Evaluation

China Postdoctoral Science Foundation

Natural Science Foundation of Guangdong Province

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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