Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy

Leverson, Joel D.; Phillips, Darren C.; Mitten, Michael J.; Boghaert, Erwin R.; Diaz, Dolores; Tahir, Stephen K.; Belmont, Lisa D.; Nimmer, Paul; Xiao, Yu; Ma, Xiaoju Max; Lowes, Kym N.; Kovar, Peter; Chen, Jun; Jin, Sha; Smith, Morey; Xue, John; Zhang, Haichao; Oleksijew, Anatol; Magoc, Terrance J.; Vaidya, Kedar S.; Albert, Daniel H.; Tarrant, Jacqueline M.; La, Nghi; Wang, Le; Tao, Zhi-Fu; Wendt, Michael D.; Sampath, Deepak; Rosenberg, Saul H.; Tse, Chris; S. Huang, David C.; Fairbrother, Wayne J.; Elmore, Steven W.; Souers, Andrew J.

doi:10.1126/scitranslmed.aaa4642

Cited by 548Cell death mechanisms and regulationCancer-related Molecular PathwaysChronic Lymphocytic Leukemia Research

Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy

Leverson, Joel D., Phillips, Darren C., Mitten, Michael J., Boghaert, Erwin R., Diaz, Dolores, Tahir, Stephen K., Belmont, Lisa D., Nimmer, Paul +25 more·2015·Science Translational Medicine

DOI 10.1126/scitranslmed.aaa4642

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Abstract

Selective inhibition of BCL-X L synergizes with docetaxel to inhibit the growth of solid tumors but does not inhibit granulopoiesis.

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The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity.
“The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [25]
Bcl-xl inhibition with ABT263 and other small molecular inhibitors induces platelet apoptosis and results in severe thrombocytopenia, which prevents the use of ABT263 and other Bcl-xl specific inhibitors in the clinic even for cancer patients because platelets solely depend on Bcl-xl for survival.
“Bcl-xl inhibition with ABT263 and other small molecular inhibitors induces platelet apoptosis and results in severe thrombocytopenia, which prevents the use of ABT263 and other Bcl-xl specific inhibitors in the clinic—even for cancer patients—because platelets solely depend on Bcl-xl for survival24–27.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [25]
ABT263 is highly toxic to both WI38 IR-SCs and platelets.
“As reported, ABT263 was highly toxic to both WI38 IR-SCs (Fig. 1g, middle panel) and platelets16–18,24–27 (Fig. 1g, right panel; Supplementary Fig. 2).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [25]
Both senescent cells and platelets, but not non-senescent cells, are primarily dependent on Bcl-xl for survival.
“Because both SCs and platelets, but not NCs, are primarily dependent on Bcl-xl for survival16–18,24–27 (Supplementary Fig. 1h), we evaluated the effects of PZ compared with ABT263 on the viability of WI38 NCs (Fig. 1g, left panel), IR-SCs (Fig. 1g, middle panel), and platelets (Fig. 1g, right panel).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [25]
PZ can selectively induce apoptosis in senescent cells, but not platelets, which are dependent on Bcl-xl for survival while having minimal toxicity to non-senescent cells that are less sensitive to Bcl-xl inhibition than senescent cells.
“Therefore, PZ can selectively induce apoptosis in SCs, but not platelets, which are dependent on Bcl-xl for survival while having minimal toxicity to NCs that are less sensitive to Bcl-xl inhibition than SCs16–18,24–27.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [25]

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Authors: Leverson, J. D., Phillips, D. C., Mitten, M. J., Boghaert, E. R., Diaz, D., Tahir, S. K., Belmont, L. D., Nimmer, P., Xiao, Y., Ma, X. M., Lowes, K. N., Kovar, P., Chen, J., Jin, S., Smith, M., Xue, J., Zhang, H., Oleksijew, A., Magoc, T. J., Vaidya, K. S., Albert, D. H., Tarrant, J. M., La, N., Wang, L., Tao, Z.-F., Wendt, M. D., Sampath, D., Rosenberg, S. H., Tse, C., S. Huang, D. C., Fairbrother, W. J., Elmore, S. W., & Souers, A. J.
Affiliations: AbbVie (United States) (US)
Genentech (US)
AbbVie Inc., North Chicago, IL 60064, USA.
The University of Melbourne (AU)
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Corresponding author: Leverson, Joel D.
Ma, Xiaoju Max
ORCID: Leverson, Joel D.
Phillips, Darren C.
Boghaert, Erwin R.
Tahir, Stephen K.
Nimmer, Paul
Lowes, Kym N.
Kovar, Peter
Chen, Jun
Jin, Sha
Zhang, Haichao
Vaidya, Kedar S.
Wang, Le
Tao, Zhi-Fu
Wendt, Michael D.
Sampath, Deepak
Tse, Chris
Fairbrother, Wayne J.
Souers, Andrew J.
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2015-03-18
Volume: 7
Issue: 279
Pages: 279ra40-279ra40
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.aaa4642
OpenAlex: W2110525250
Cited by: 541
References: 51
Citations by year: 2026: 22 · 2025: 33 · 2024: 34 · 2023: 38 · 2022: 58 · 2021: 56 · 2020: 69 · 2019: 49 · 2018: 58 · 2017: 65 · 2016: 43 · 2015: 12
FWCI: 25.92
Type: journal article
Language: en
Open access: closed
Licence: www.sciencemag.org/about/science-licenses-journal-article-reuse (vor, 366 d)
Locations: Science Translational Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: Leukemia and Lymphoma Society
Medical Research Council (461219, 461221, 1016701)
Australian Cancer Research Foundation
Cancer Council Victoria
Australian National Health
Independent Research Institutes Infrastructure Support Scheme (361646)
Victorian State Government Operational Infrastructure Support
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Keywords: BCL-2 inhibitor, venetoclax, navitoclax, BCL-XL inhibition, A-1331852, docetaxel combination, neutropenia, thrombocytopenia, granulopoiesis, solid tumors, chronic lymphocytic leukemia
MeSH terms: Docetaxel, Administration, Oral, Aniline Compounds, Animals, Antineoplastic Agents, Cell Survival, Granulocytes, Humans, Isoquinolines, Kinetics, Neoplasm Transplantation, Neoplasms, Neutropenia, Neutrophils, Sulfonamides, Thrombocytopenia, Gene Expression Regulation, Neoplastic, Bridged Bicyclo Compounds, Heterocyclic, Proto-Oncogene Proteins c-bcl-2, Gene Expression Profiling, Taxoids, Cell Line, Tumor, bcl-X Protein, Mice, Benzothiazoles

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Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy

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