FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non-Small Cell Lung Cancer
FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non-Small Cell Lung Cancer
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DOI：
10.1158/1078-0432.ccr-22-0791
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发表时间：
2022-09-01
影响因子：
11.5
通讯作者：
Zhang, Li
中科院分区：
文献类型：
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作者：
Guan, Shaoxing;Chen, Xi;Zhang, Li
目的：吉非替尼虽然延长了无进展生存期，但仍急需机制明确的生物标志物。实验设计：共282例接受吉非替尼治疗的NSCLC患者以7：3的比例随机分配至探索性（n = 192）和验证性（n = 90）队列。应用Hapmap中的Haploview4.2软件筛选候选多态性，MassARRAY系统进行基因分型，并进行分析。通过Tanswell和克隆形成试验、碱基编辑和细胞源性肿瘤异种移植模型来揭示潜在的结果：我们发现生殖系错义多态性rs3742076（A > G，S628 P），位于FOXM 1的反式激活结构域，在探索性研究中与PFS相关。37个月，P = 0.00039，HR = 2.399）和验证（中位PFS：GG vs. GA & AA，8.13 vs. 13.80个月，P = 0.048，HR = 2.628）队列。我们阐明rs3742076_G通过增加FOXM 1的蛋白稳定性并通过激活wnt/β-catenin信号通路在体外和体内促进侵袭性表型而赋予吉非替尼抗性。同时，FOXM 1水平与EGFR突变型NSCLC患者的预后高度相关。FOXM 1 rs3742076_G通过直接与细胞质中的β-catenin结合并促进细胞核中的β-catenin转录来上调wnt/β-catenin活性。值得注意的是，β-连环蛋白的抑制显著逆转了rs3742076_G诱导的吉非替尼耐药性和侵袭性表型。结论：这些发现将rs3742076_G表征为介导吉非替尼耐药和肿瘤侵袭性的功能获得性多态性，并强调该变体作为指导吉非替尼治疗的预测性生物标志物。
Purpose: Although gefitinib prolonged the progression-free tive 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 analysis. Tanswell and clonogenic assays, base editing and cell-derived tumor xenograft model were performed to uncover the underlying 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/beta-catenin signaling pathway. Meanwhile, FOXM1 level was highly associated with prognosis in patients with EGFR-mutant NSCLC. Mechanistically, FOXM1 rs3742076_G upregulated wnt/beta-catenin activity by directly binding to beta-catenin in cytoplasm and promoting transcription of beta-catenin in nucleus. Remarkably, inhibition of beta-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.