FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non-Small Cell Lung Cancer
©2022 American Association for Cancer Research..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 28(2022), 17 vom: 01. Sept., Seite 3770-3784 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Guan, Shaoxing [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 08.09.2022 Date Revised 10.06.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-22-0791 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM342174886 |
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| 100 | 1 | |a Guan, Shaoxing |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non-Small Cell Lung Cancer |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 08.09.2022 | ||
| 500 | |a Date Revised 10.06.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2022 American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Chen, Youhao |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Heng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Xia |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yunpeng |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Wenfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Hongyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xueding |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Li |e verfasserin |4 aut | |
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