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Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer
Open accessAbstract
Significance: Small-cell lung cancer (SCLC) is an aggressive carcinoma with few effective treatment options beyond first-line chemotherapy. BH3 mimetics, such as ABT-263, promote apoptosis in SCLC cell lines, but early phase clinical trials demonstrated no significant clinical benefit. Here, we examine the sensitivity of a large panel of cancer cell lines, including SCLC, to ABT-263 and find that high Bcl2-interacting mediator of cell death (BIM) and low myeloid cell leukemia 1 (MCL-1) expression together predict sensitivity. SCLC cells relatively resistant to ABT-263 are sensitized by TORC1/2 inhibition via MCL-1 reduction. Combination of ABT-263 and TORC1/2 inhibition stabilizes or shrinks tumors in xenograft models, in autochthonous SCLC tumors in a genetically engineered mouse model, and in a patient-derived xenograft SCLC model. Collectively, these data support a compelling new therapeutic strategy for treating SCLC.
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“There is a growing body of evidence suggesting that deficient apoptosis induction following targeted therapy treatments can lead to a lack of efficacy”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [38]
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“The same model has also been used to test the efficacy of anti-apoptotic inhibitors both as single agents and in a combination regimen (Faber et al. 2015).”
BackgroundMethodRegulation of Bim in Health and Disease
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“Small-cell lung cancer (SCLC) with high Bim expression is among the most sensitive cells to ABT-263 treatment [584].”
Background
Metadata
- Authors
- Faber, A. C., Farago, A. F., Costa, C., Dastur, A., Gomez-Caraballo, M., Robbins, R., Wagner, B. L., Rideout, W. M., Jakubik, C. T., Ham, J., Edelman, E. J., Ebi, H., Yeo, A. T., Hata, A. N., Song, Y., Patel, N. U., March, R. J., Tam, A. T., Milano, R. J., Boisvert, J. L., Hicks, M. A., Elmiligy, S., Malstrom, S. E., Rivera, M. N., Harada, H., Windle, B. E., Ramaswamy, S., Benes, C. H., Jacks, T., & Engelman, J. A.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital Cancer Center, Boston, MA 02129;
- Koch Institute for Integrative Cancer Research At MIT (US)
- Virginia Commonwealth University (US)
- Massachusetts General Hospital (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-03-03
- Volume
- 112
- Issue
- 11
- Pages
- E1288-96
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4371986
- OpenAlex
- W1981797550
- Cited by
- 127
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 10 · 2022: 9 · 2021: 9 · 2020: 15 · 2019: 14 · 2018: 21 · 2017: 15 · 2016: 13 · 2015: 7
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- HHS | NIH | National Cancer Institute (2P50 CA09057, R01CA40594, R01CA137008-01, 1U54HG006097-1, P30-CA14051)
- U.S. Department of Defense (W81-XWH-13-1-0325)
- Burroughs Wellcome Fund (n/a)
- American Cancer Society (n/a)
- Uniting Against Lung Cancer (n/a)
- Lung Cancer Research Foundation (n/a)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- navitoclax, venetoclax, BH3 mimetics, small cell lung cancer, building information modeling, Mcl-1, Bcl-2, Bcl-xL, apoptosis, combination therapy, AZD8055, rapamycin, drug resistance, cancer cell line sensitivity, patient-derived xenografts, genetically engineered mouse models
- MeSH terms
- Bcl-2-Like Protein 11, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Aniline Compounds, Animals, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Genetic Engineering, Humans, Lung Neoplasms, Membrane Proteins, Morpholines, Proto-Oncogene Proteins, Remission Induction, Sulfonamides, Apoptosis, Inhibitory Concentration 50, Xenograft Model Antitumor Assays, Cell Line, Tumor, Multiprotein Complexes, Apoptosis Regulatory Proteins, Mice, Small Cell Lung Carcinoma, TOR Serine-Threonine Kinases, Myeloid Cell Leukemia Sequence 1 Protein
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