期刊
CLINICAL CANCER RESEARCH
卷 24, 期 1, 页码 197-208出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-1577
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资金
- George and Lavinia Blick Research Fund
- American Lung Association Lung Cancer Discovery Award
- Career Development Award [NCIK22-CA175276]
- Uniting Against Lung Cancer
- Lung Cancer Research Foundation
- Department of Defense grant
- American Cancer Society Institutional Grant
- Japan Agency for Medical Research and Development (Project for Cancer Research and Therapeutics Evolution) [16cm0106513h0001]
- KAKENHI [16K07164]
- National Institute of Dental and Craniofacial Research grant [DE025037]
- Grants-in-Aid for Scientific Research [16K07164] Funding Source: KAKEN
Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mecha-nistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance free cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship betweenEMTand loss of BIMis not restricted toEGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. (C) 2017 AACR.
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