SI Table 2 from Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM

Song, Kyung-A; Niederst, Matthew J.; Lochmann, Timothy L.; Hata, Aaron N.; Kitai, Hidenori; Ham, Jungoh; Floros, Konstantinos V.; Hicks, Mark A.; Hu, Haichuan; Mulvey, Hillary E.; Drier, Yotam; Heisey, Daniel A.R.; Hughes, Mark T.; Patel, Neha U.; Lockerman, Elizabeth L.; Garcia, Angel; Gillepsie, Shawn; Archibald, Hannah L.; Gomez-Caraballo, Maria; Nulton, Tara J.; Windle, Brad E.; Piotrowska, Zofia; Sahingur, Sinem E.; Taylor, Shirley M.; Dozmorov, Mikhail; Sequist, Lecia V.; Bernstein, Bradley; Ebi, Hiromichi; Engelman, Jeffrey A.; Faber, Anthony C.

doi:10.1158/1078-0432.22462241.v1

SI Table 2 from Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM

journal contribution

posted on 2023-03-31, 19:22 authored by Kyung-A Song, Matthew J. Niederst, Timothy L. Lochmann, Aaron N. Hata, Hidenori Kitai, Jungoh Ham, Konstantinos V. Floros, Mark A. Hicks, Haichuan Hu, Hillary E. Mulvey, Yotam Drier, Daniel A.R. Heisey, Mark T. Hughes, Neha U. Patel, Elizabeth L. Lockerman, Angel Garcia, Shawn Gillepsie, Hannah L. Archibald, Maria Gomez-Caraballo, Tara J. Nulton, Brad E. Windle, Zofia Piotrowska, Sinem E. Sahingur, Shirley M. Taylor, Mikhail Dozmorov, Lecia V. Sequist, Bradley Bernstein, Hiromichi Ebi, Jeffrey A. Engelman, Anthony C. Faber

ZEB1 binding sites found in 1975R2 cells compared to 1975 parental cells

Funding

George and Lavinia Blick Research Fund

American Lung Association Lung Cancer Discovery Award

Department of Defense

American Cancer Society Institutional Grant

Cancer Research and Therapeutics Evolution

National Institute of Dental and Craniofacial Research

History

ARTICLE ABSTRACT

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. Clin Cancer Res; 24(1); 197–208. ©2017 AACR.