TY - JOUR
T1 - Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM
AU - Song, Kyung A.
AU - Niederst, Matthew J.
AU - Lochmann, Timothy L.
AU - Hata, Aaron N.
AU - Kitai, Hidenori
AU - Ham, Jungoh
AU - Floros, Konstantinos V.
AU - Hicks, Mark A.
AU - Hu, Haichuan
AU - Mulvey, Hillary E.
AU - Drier, Yotam
AU - Heisey, Daniel A.R.
AU - Hughes, Mark T.
AU - Patel, Neha U.
AU - Lockerman, Elizabeth L.
AU - Garcia, Angel
AU - Gillepsie, Shawn
AU - Archibald, Hannah L.
AU - Gomez-Caraballo, Maria
AU - Nulton, Tara J.
AU - Windle, Brad E.
AU - Piotrowska, Zofia
AU - Sahingur, Sinem E.
AU - Taylor, Shirley M.
AU - Dozmorov, Mikhail
AU - Sequist, Lecia V.
AU - Bernstein, Bradley
AU - Ebi, Hiromichi
AU - Engelman, Jeffrey A.
AU - Faber, Anthony C.
N1 - Publisher Copyright:
© 2017 AACR.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040084785&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-1577
DO - 10.1158/1078-0432.CCR-17-1577
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C2 - 29051323
AN - SCOPUS:85040084785
SN - 1078-0432
VL - 24
SP - 197
EP - 208
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -