journal contribution
posted on 2023-03-31, 23:40 authored by 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 Supplementary Table from FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non–Small Cell Lung Cancer
Funding
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
History
ARTICLE ABSTRACT
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.
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.
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.
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.
