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FOXM1 variant contributes to gefitinib resistance via activating wnt/β-catenin signal pathway in non-small cell lung cancer patients.

PURPOSE
Although gefitinib prolonged the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients, unpredictable resistance limited its clinical efficacy. Novel predictive biomarkers with explicit mechanisms are urgently needed.


EXPERIMENTAL DESIGN
A total of 282 NSCLC patients 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. Tans-well 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 EGFR-mutant NSCLC patients. 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.


CONCLUSION
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.