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. Mechanistically, 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 between EMT and loss of BIM is not restricted to EGFR-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.
Bibliographical noteFunding Information:
A.C. Faber is supported by the George and Lavinia Blick Research Fund.
This work was supported by an American Lung Association Lung Cancer Discovery Award (to A.C. Faber), a NCIK22-CA175276 Career Development Award (to A.C. Faber), Uniting Against Lung Cancer (to M.J. Niederst), the Lung Cancer Research Foundation (to M.J. Niederst), a Department of Defense grant (to J.A. Engelman and L.V. Sequist), an American Cancer Society Institutional Grant (to A.C. Faber), a Grant-in-Aid from the Japan Agency for Medical Research and Development (Project for Cancer Research and Therapeutics Evolution; 16cm0106513h0001), a Grant-in-Aid for Scientific Research (KAKENHI 16K07164) to H. Ebi, and a National Institute of Dental and Craniofacial Research grant (DE025037) to S.E. Sahingur.
A.N. Hata reports receiving commercial research grants from Amgen, Novar-tis and Relay Therapeutics. Z. Piotrowska is a consultant/advisory board member for Ariad Pharmaceuticals, AstraZeneca, and Guardant Health. L.V. Sequist is a consultant/advisory board member for Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Genentech, Merrimack, Novartis, and Pfizer. J.A. Engelman is an employee of and has ownership interests (including patents) at Novartis. No potential conflicts of interest were disclosed by the other authors.
© 2017 AACR.