Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM
Open accessPublished version of a preprint
Abstract
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.
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Resistant mesenchymal EGFR-mutant lung cancers exhibit an apoptotic defect due to loss of BIM expression, leading to loss of cell death despite effective suppression of oncogenic signaling by targeted therapy.
“Song et al. observed that resistant mesenchymal EGFR-mutant lung cancers exhibit an apoptotic defect due to loss of BIM expression, leading to loss of a cell death despite effective suppression of oncogenic signaling by targeted therapy [117].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [117]
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References 60 · Cited by 95
- Authors
- 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., Nulton, T. J., Windle, B. E., Piotrowska, Z., Sahingur, S. E., Taylor, S. M., Dozmorov, M., Sequist, L. V., Bernstein, B., Ebi, H., Engelman, J. A., & Faber, A. C.
- Affiliations
- Virginia Commonwealth University (US)
- Harvard University (US)
- Kanazawa University (JP)
- 2Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
- VCU Massey Comprehensive Cancer Center (US)
- Corresponding author
- Engelman, Jeffrey A.
- Faber, Anthony C.
- ORCID
- Niederst, Matthew J.
- Lochmann, Timothy L.
- Hata, Aaron N.
- Kitai, Hidenori
- Floros, Konstantinos V.
- Hu, Haichuan
- Mulvey, Hillary E.
- Drier, Yotam
- Heisey, Daniel A.R.
- Patel, Neha U.
- Lockerman, Elizabeth L.
- Piotrowska, Zofia
- Sahingur, Sinem E.
- Taylor, Shirley M.
- Dozmorov, Mikhail
- Sequist, Lecia V.
- Bernstein, Bradley
- Ebi, Hiromichi
- Engelman, Jeffrey A.
- Faber, Anthony C.
- Venue
- Clinical Cancer Research
- Published
- 2018-01-01
- Volume
- 24
- Issue
- 1
- Pages
- 197-208
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5959009
- OpenAlex
- W2767109827
- Cited by
- 95
- References
- 60
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 8 · 2023: 10 · 2022: 10 · 2021: 16 · 2020: 14 · 2019: 15 · 2018: 9
- FWCI
- 8.59
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (15KK0303, 16K07164)
- National Cancer Institute (K22CA175276, K08CA197389)
- National Institute of Dental and Craniofacial Research (R01DE025037)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- epithelial-mesenchymal transition, EGFR inhibitors, EGFR-mutant lung cancer, building information modeling, apoptosis resistance, ZEB1, transcriptional repression, navitoclax, BH3 mimetics, KRAS-mutant lung cancer, targeted therapy resistance, drug re-sensitization
- MeSH terms
- Bcl-2-Like Protein 11, Aniline Compounds, Animals, Cell Cycle, Disease Models, Animal, Humans, Lung Neoplasms, Mutation, Promoter Regions, Genetic, Sulfonamides, Gene Expression Regulation, Neoplastic, Apoptosis, Drug Resistance, Neoplasm, RNA, Small Interfering, Protein Kinase Inhibitors, Mice, Epithelial-Mesenchymal Transition, Molecular Targeted Therapy, ErbB Receptors
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