Germline USP36 Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non-Small Cell Lung Cancer
©2024 American Association for Cancer Research..
PURPOSE: Although somatic mutations were explored in depth, limited biomarkers were found to predict the resistance of EGFR tyrosine kinase inhibitors (EGFR-TKI). Previous studies reported N6-methyladenosine (m6A) levels regulated response of EGFR-TKIs; whether the germline variants located in m6A sites affected resistance of EGFR-TKIs is still unknown.
EXPERIMENTAL DESIGN: Patients with non-small cell lung cancer (NSCLC) with EGFR-activating mutation were enrolled to investigate predictors for response of EGFR-TKIs using a genome-wide-variant-m6A analysis. Bioinformatics analysis and series of molecular biology assays were used to uncover the underlying mechanism.
RESULTS: We identified the germline mutation USP36 rs3744797 (C > A, K814N) was associated with survival of patients with NSCLC treated with gefitinib [median progression-free survival (PFS): CC vs. CA, 16.30 vs. 10.50 months, P < 0.0001, HR = 2.45] and erlotinib (median PFS: CC vs. CA, 14.13 vs. 9.47 months, P = 0.041, HR = 2.63). Functionally, the C > A change significantly upregulated USP36 expression by reducing its m6A level. Meanwhile, rs3744797_A (USP36 MUT) was found to facilitate proliferation, migration, and resistance to EGFR-TKIs via upregulating MLLT3 expression in vitro and in vivo. More importantly, MLLT3 and USP36 levels are tightly correlated in patients with NSCLC, which were associated with prognosis of patients. Mechanistically, USP36 MUT stabilized MLLT3 by deubiquitinating MLLT3 in nucleoli and consequently activating its downstream signaling (HIF1α and Snai). Furthermore, inhibition of MLLT3 alleviated USP36 variant-induced EGFR-TKIs resistance in EGFR-mutant NSCLC.
CONCLUSIONS: These findings characterized rs3744797 as an oncogenic variant in mediating EGFR-TKI resistance and tumor aggressiveness through deubiquitinating MLLT3, highlighting the variant as a predictive biomarker for EGFR-TKI response in NSCLC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 30(2024), 7 vom: 01. Apr., Seite 1382-1396 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Guan, Shaoxing [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.7.10.1 |
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| Anmerkungen: |
Date Completed 03.04.2024 Date Revised 08.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-23-2357 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367519542 |
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| 100 | 1 | |a Guan, Shaoxing |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Germline USP36 Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non-Small Cell Lung Cancer |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 03.04.2024 | ||
| 500 | |a Date Revised 08.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2024 American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Although somatic mutations were explored in depth, limited biomarkers were found to predict the resistance of EGFR tyrosine kinase inhibitors (EGFR-TKI). Previous studies reported N6-methyladenosine (m6A) levels regulated response of EGFR-TKIs; whether the germline variants located in m6A sites affected resistance of EGFR-TKIs is still unknown | ||
| 520 | |a EXPERIMENTAL DESIGN: Patients with non-small cell lung cancer (NSCLC) with EGFR-activating mutation were enrolled to investigate predictors for response of EGFR-TKIs using a genome-wide-variant-m6A analysis. Bioinformatics analysis and series of molecular biology assays were used to uncover the underlying mechanism | ||
| 520 | |a RESULTS: We identified the germline mutation USP36 rs3744797 (C > A, K814N) was associated with survival of patients with NSCLC treated with gefitinib [median progression-free survival (PFS): CC vs. CA, 16.30 vs. 10.50 months, P < 0.0001, HR = 2.45] and erlotinib (median PFS: CC vs. CA, 14.13 vs. 9.47 months, P = 0.041, HR = 2.63). Functionally, the C > A change significantly upregulated USP36 expression by reducing its m6A level. Meanwhile, rs3744797_A (USP36 MUT) was found to facilitate proliferation, migration, and resistance to EGFR-TKIs via upregulating MLLT3 expression in vitro and in vivo. More importantly, MLLT3 and USP36 levels are tightly correlated in patients with NSCLC, which were associated with prognosis of patients. Mechanistically, USP36 MUT stabilized MLLT3 by deubiquitinating MLLT3 in nucleoli and consequently activating its downstream signaling (HIF1α and Snai). Furthermore, inhibition of MLLT3 alleviated USP36 variant-induced EGFR-TKIs resistance in EGFR-mutant NSCLC | ||
| 520 | |a CONCLUSIONS: These findings characterized rs3744797 as an oncogenic variant in mediating EGFR-TKI resistance and tumor aggressiveness through deubiquitinating MLLT3, highlighting the variant as a predictive biomarker for EGFR-TKI response in NSCLC | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a USP36 protein, human |2 NLM | |
| 700 | 1 | |a Chen, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Yuru |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Youhao |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 Zhang, Xiaoxu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Wei |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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