The DOI matches its Crossref record; 45 of the 46 references it cites were found in a registry or an index.
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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Citations
Cites
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
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Self-citationABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
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Programmed Anuclear Cell Death Delimits Platelet Life Span
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“ABT-263 was well tolerated in the clinic with a dose-limiting toxicity of thrombocytopenia (22), an on-target toxicity of BCL-XL inhibition (23).”
BackgroundRoberts, A. W., Seymour, J. F., Brown, J. R., Wierda, W. G., Kipps, T. J., Khaw, S. L., Carney, D. A., He, S., Huang, D. C. S., Xiong, H., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.34.7898 · Cited by 855
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Cited by
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Items 101–125 of 125
Maruyama, A., Sato, Y., Nakayama, J., Murai, J., Ishikawa, T., Soga, T., & Makinoshima, H. (2021) · Scientific Reports · doi:10.1038/s41598-021-92948-9 · Cited by 10
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“*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, not significant [60], possibly by binding to the pro-apoptotic proteins BIM and BAX [37, 40, 43] (Supplementary Fig.”
BackgroundInfluentialEffective Targeting of Melanoma Cells by Combination of Mcl-1 and Bcl-2/Bcl-xL/Bcl-w Inhibitors
Peng, Z., Gillissen, B. F., Richter, A., Sinnberg, T. W., Schlaak, M. S., & Eberle, J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063453 · Cited by 7
“High levels of Mcl-1 may further correlate with resistance to ABTs, as reported for cells of ALL [59], CLL [60], and lung and breast cancers [61,62].”
BackgroundBcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
Westhoff, M., Schuler-Ortoli, M., Zerrinius, D., Hadzalic, A., Schuster, A., Strobel, H., Scheuerle, A., Wong, T., Wirtz, C. R., Debatin, K., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15010091 · Cited by 7
“ABT-263 exhibited a diverse effect on the four cell lines when used at low micromolar concentrations, a concentration range also identified in other malignant cells as effective [22].”
BackgroundBH3 mimetics and TKI combined therapy for Chronic Myeloid Leukemia
Brumatti, G., Kaloni, D., de Castro, F. A., & Amarante-Mendes, G. P. (2023) · Biochemical Journal · doi:10.1042/bcj20210608 · Cited by 8
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“The finding thatMCL-1 expression is regulated bymTORC1 in TSC-deficient settings is consistent with preclinical studies of other cancers.(35,41,49,54) However, a caveat with these previous studies is that catalytic domain inhibitors of mTORC1 and/or PI3K, and even rapamycin in some settings, also influenced the activa…”
ResultTobramycin suppresses HUWE1 degradation to control MCL‐1 stability during tumour development
He, J., Wu, S., Li, X., Tang, L., Chen, H., Qin, L., Xie, J., Lü, T., & Xu, W. (2020) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13335 · Cited by 6
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“…of both TORC1 and TORC2, such as AZD8055, can suppresses downstream MCL-1 translation, thereby more globally dampening anti-apoptotic signaling pathways, and demonstrated excellent preclinical activity when combined with navitoclax in PDX and genetically modified mouse models of SCLC [19].”
Self-citationOgino, A., Vajdi, A., Mu, X. J., Mahadevan, N. R., Ngo, K. H., Booker, M. A., Cejas, P., Okoro, J. J., Xu, M., Springer, B. F., et al. (2026) · JCI Insight · doi:10.1172/jci.insight.197008 · Cited by 5
“As navitoclax and JQ-1 both have an antitumor efficacy on SCLC models (42, 43), we selected these 2 compounds along with cisplatin from the 32 drugs used for screening (Figure 6A) to test the combination effect with trametinib in vitro.”
Li, L., Li, P., Song, H., Ma, X., Zeng, S., Peng, Y., & Zhang, G. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106095 · Cited by 5
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Lee, Y., Wang, L., Huang, C., Chiou, J., Shi, Y., & Chang, L. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114047 · Cited by 3
Mitochondrial involvement in PC: improving therapeutic strategies
Zhang, J., & Lou, C. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1710923 · Cited by 2
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“However, unlike our and others’ published reports that mTOR inhibition causes MCL-1 suppression in various tumor cell lines [29,40,41], everolimus did not alter the expression of MCL-1 in the G12D-mutated PDAC cell lines (Supplementary Figure S4g–i).”
Small cell lung cancer: an overview of the targets
Valadares, B. N., & Stephano, M. A. (2022) · Brazilian Journal of Pharmaceutical Sciences · doi:10.1590/s2175-97902022e19114 · Cited by 2
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“Indeed, preclinical studies indicate that navitoclax may be 50 efficacious in solid tumors when used in combination with other agents acting through a variety 51 of mechanisms, including by decreasing MCL1 expression (11,16-22).”
BackgroundInfluentialmRNA lipid-nanoparticle-mediated mitochondrial apoptosis augments adoptive T cell immunotherapy
Fu, J., Liu, Y., Zhong, Z., Cao, B., Ran, L., Guo, Z., Dong, H., Bao, N., Pan, R. A., Wang, J., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102706 · Cited by 2
Sensitivity and Resistance to BH3 Mimetics in Cancer Therapy
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Self-citationPeckham-Cooper, A. (2017) · White Rose eTheses Online (University of Leeds, The University of Sheffield, University of York)
Leto, S. M., Ferri, M., Sassi, F. P., Zanella, E. R., Cottino, F., Vurchio, V., Catalano, I., Ferrero, A., Zingaretti, C. C., Marchiò, C., et al. (2023) · doi:10.1158/1078-0432.c.6533128.v1
Data from NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263
Dastur, A., Choi, A., Costa, C., Yin, X., Williams, A. F., McClanaghan, J., Greenberg, M., Roderick, J. E., Patel, N. U., Boisvert, J. L., et al. (2023) · doi:10.1158/1078-0432.c.6528492.v1
Self-citationLake, B., Banerjee, A., Cuffee, J., Banerjee, N., Armstrong, E., Banerjee, S., Blount, C., Hunter, C., El-Hashash, A. H. K., Rawat, K. S., et al. (2025) · Computational Molecular Bioscience · doi:10.4236/cmb.2025.152002
“Finally, EIF4A1P5 is an initiation factor in the 43 ribosome that assists with cytoplasmic translation and is found to have oncogenic properties in lung cancers [8].”
Cornu, M., Pezeril, J., Guedeney, N., Paysant, H., Lemaitre, T., Schwalen, F., Florent, R., N’Guyen, J., Corvaisier, S., Since, M., et al. (2026) · European Journal of Medicinal Chemistry Reports · doi:10.1016/j.ejmcr.2026.100336
BindingDB Entry 50009085: The chemical biology of apoptosis: Revisited after 17 years.
BindingDB (2021) · UC San Diego · doi:10.7270/q2r78jmk
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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