Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

Overview

Journal Cancer Discov

Specialty Oncology

Date 2022 May 2

PMID 35491624

Authors

Joan Montero

Rizwan Haq

Affiliations

Soon will be listed here.

Abstract

Significance: Targeting antiapoptotic family members has proven efficacious and tolerable in some cancers, but responses are infrequent, particularly for patients with solid tumors. Biomarkers to aid patient selection have been lacking. Precision functional approaches that overcome adaptive resistance to these compounds could drive durable responses to chemotherapy, targeted therapy, and immunotherapies.

Citing Articles

Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer.

Zhang L, Wei Y, Luo M, Ren S, Zhan X, Wang C Cell Death Dis. 2025; 16(1):170.

PMID: 40075071 PMC: 11904182. DOI: 10.1038/s41419-025-07481-8.

Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.

Lopez J, Llop-Hernandez A, Verdura S, Serrano-Hervas E, Martinez-Balibrea E, Bosch-Barrera J Cell Death Discov. 2025; 11(1):91.

PMID: 40055336 PMC: 11889205. DOI: 10.1038/s41420-025-02379-y.

Tipping the balance of cell death: alternative splicing as a source of MCL-1S in cancer.

Hartman M Cell Death Dis. 2024; 15(12):917.

PMID: 39695189 PMC: 11655658. DOI: 10.1038/s41419-024-07307-z.

HRK downregulation and augmented BCL-xL binding to BAK confer apoptotic protection to therapy-induced senescent melanoma cells.

Alcon C, Kovatcheva M, Morales-Sanchez P, Lopez-Polo V, Torres T, Puig S Cell Death Differ. 2024; .

PMID: 39627361 DOI: 10.1038/s41418-024-01417-z.

Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.

Cuyas E, Pedarra S, Verdura S, Pardo M, Espin Garcia R, Serrano-Hervas E Cell Death Discov. 2024; 10(1):417.

PMID: 39349429 PMC: 11442875. DOI: 10.1038/s41420-024-02184-z.

References

Thangavadivel S, Byrd J . Gly101Val BCL2 Mutation: One Step Closer to Understanding Venetoclax Resistance in CLL. Cancer Discov. 2019; 9(3):320-322. DOI: 10.1158/2159-8290.CD-19-0029. View

Lee E, Harris T, Tran S, Evangelista M, Arulananda S, John T . BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival. Cell Death Dis. 2019; 10(5):342. PMC: 6482196. DOI: 10.1038/s41419-019-1568-3. View

Merino D, Whittle J, Vaillant F, Serrano A, Gong J, Giner G . Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer. Sci Transl Med. 2017; 9(401). DOI: 10.1126/scitranslmed.aam7049. View

Chen L, Willis S, Wei A, Smith B, Fletcher J, Hinds M . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005; 17(3):393-403. DOI: 10.1016/j.molcel.2004.12.030. View

Karlsson H . Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery. Biochem Soc Trans. 2016; 44(2):371-6. DOI: 10.1042/BST20150253. View

Montero J, Sarosiek K, DeAngelo J, Maertens O, Ryan J, Ercan D . Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell. 2015; 160(5):977-989. PMC: 4391197. DOI: 10.1016/j.cell.2015.01.042. View

Sarosiek K, Fraser C, Muthalagu N, Bhola P, Chang W, McBrayer S . Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell. 2016; 31(1):142-156. PMC: 5363285. DOI: 10.1016/j.ccell.2016.11.011. View

Leverson J, Zhang H, Chen J, Tahir S, Phillips D, Xue J . Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 2015; 6:e1590. PMC: 4669759. DOI: 10.1038/cddis.2014.561. View

Garciaz S, Guirguis A, Muller S, Brown F, Chan Y, Motazedian A . Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death. Cancer Discov. 2021; 12(3):774-791. PMC: 9390741. DOI: 10.1158/2159-8290.CD-21-0522. View

10.

Pan R, Hogdal L, Benito J, Bucci D, Han L, Borthakur G . Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2013; 4(3):362-75. PMC: 3975047. DOI: 10.1158/2159-8290.CD-13-0609. View

11.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

12.

Nechiporuk T, Kurtz S, Nikolova O, Liu T, Jones C, DAlessandro A . The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells. Cancer Discov. 2019; 9(7):910-925. PMC: 6606338. DOI: 10.1158/2159-8290.CD-19-0125. View

13.

DiNardo C, Lachowiez C, Takahashi K, Loghavi S, Xiao L, Kadia T . Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia. J Clin Oncol. 2021; 39(25):2768-2778. PMC: 8407653. DOI: 10.1200/JCO.20.03736. View

14.

Sheridan C, Brumatti G, Martin S . Oncogenic B-RafV600E inhibits apoptosis and promotes ERK-dependent inactivation of Bad and Bim. J Biol Chem. 2008; 283(32):22128-35. DOI: 10.1074/jbc.M800271200. View

15.

Stover E, Baco M, Cohen O, Li Y, Christie E, Bagul M . Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer. Mol Cancer Res. 2019; 17(11):2281-2293. PMC: 6825578. DOI: 10.1158/1541-7786.MCR-18-1243. View

16.

Roberts A, Davids M, Pagel J, Kahl B, Puvvada S, Gerecitano J . Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2015; 374(4):311-22. PMC: 7107002. DOI: 10.1056/NEJMoa1513257. View

17.

Wang L, Doherty G, Judd A, Tao Z, Hansen T, Frey R . Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X Inhibitor. ACS Med Chem Lett. 2020; 11(10):1829-1836. PMC: 7549103. DOI: 10.1021/acsmedchemlett.9b00568. View

18.

Takahashi R, Deveraux Q, Tamm I, Welsh K, Salvesen G, Reed J . A single BIR domain of XIAP sufficient for inhibiting caspases. J Biol Chem. 1998; 273(14):7787-90. DOI: 10.1074/jbc.273.14.7787. View

19.

Carrington E, Zhan Y, Brady J, Zhang J, Sutherland R, Anstee N . Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo. Cell Death Differ. 2017; 24(5):878-888. PMC: 5423112. DOI: 10.1038/cdd.2017.30. View

20.

Bah N, Maillet L, Ryan J, Dubreil S, Gautier F, Letai A . Bcl-xL controls a switch between cell death modes during mitotic arrest. Cell Death Dis. 2014; 5:e1291. PMC: 4611724. DOI: 10.1038/cddis.2014.251. View