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

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.

• Authors: Shaoxing Guan, Xi Chen, Youhao Chen, Wen Xie, Heng Liang, Xia Zhu, Yunpeng Yang, Wenfeng Fang, Yan Huang, Hongyun Zhao, Wei Zhuang, Shu Liu, Min Huang, Xueding Wang, Li Zhang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 17 Pg. 3770-3784 (09 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35695863 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• FOXM1 protein, human
• Forkhead Box Protein M1
• beta Catenin
• Gefitinib

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Forkhead Box Protein M1 (genetics, metabolism)
• Gefitinib (pharmacology, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Wnt Signaling Pathway
• beta Catenin (genetics, metabolism)