Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM

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. NultonBrad 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

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.

Original languageAmerican English
Pages (from-to)197-208
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number1
DOIs
StatePublished - 1 Jan 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 AACR.

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