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. 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

doi:10.1158/1078-0432.CCR-17-1577

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 journal › Article › peer-review

63 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 language	American English
Pages (from-to)	197-208
Number of pages	12
Journal	Clinical Cancer Research
Volume	24
Issue number	1
DOIs	https://doi.org/10.1158/1078-0432.CCR-17-1577
State	Published - 1 Jan 2018
Externally published	Yes

Bibliographical note

Funding Information:
A.C. Faber is supported by the George and Lavinia Blick Research Fund.

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2017 AACR.

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10.1158/1078-0432.CCR-17-1577

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Song, K. A., Niederst, M. J., Lochmann, T. L., Hata, A. N., Kitai, H., Ham, J., Floros, K. V., Hicks, M. A., Hu, H., Mulvey, H. E., Drier, Y., Heisey, D. A. R., Hughes, M. T., Patel, N. U., Lockerman, E. L., Garcia, A., Gillepsie, S., Archibald, H. L., Gomez-Caraballo, M., ... Faber, A. C. (2018). Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM. Clinical Cancer Research, 24(1), 197-208. https://doi.org/10.1158/1078-0432.CCR-17-1577

@article{d7dceefb633b40c09af9bdf975d68e39,

title = "Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM",

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.",

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

note = "Funding Information: A.C. Faber is supported by the George and Lavinia Blick Research Fund. Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2017 AACR.",

year = "2018",

month = jan,

day = "1",

doi = "10.1158/1078-0432.CCR-17-1577",

language = "American English",

volume = "24",

pages = "197--208",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "1",

}

Song, KA, Niederst, MJ, Lochmann, TL, Hata, AN, Kitai, H, Ham, J, Floros, KV, Hicks, MA, Hu, H, Mulvey, HE, Drier, Y, Heisey, DAR, Hughes, MT, Patel, NU, Lockerman, EL, Garcia, A, Gillepsie, S, Archibald, HL, Gomez-Caraballo, M, Nulton, TJ, Windle, BE, Piotrowska, Z, Sahingur, SE, Taylor, SM, Dozmorov, M, Sequist, LV, Bernstein, B, Ebi, H, Engelman, JA & Faber, AC 2018, 'Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM', Clinical Cancer Research, vol. 24, no. 1, pp. 197-208. https://doi.org/10.1158/1078-0432.CCR-17-1577

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 - Funding Information: A.C. Faber is supported by the George and Lavinia Blick Research Fund. Funding Information: 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. Funding Information: 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. 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.

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U2 - 10.1158/1078-0432.CCR-17-1577

DO - 10.1158/1078-0432.CCR-17-1577

M3 - Article

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 -

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

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