Skip to main content
SpringerLink
Log in

Targeting Bcl-2 Family Proteins: What, Where, When?

  • REVIEW
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Proteins of the Bcl-2 family are known as regulators of apoptosis, one of the most studied forms of programmed cell death. The Bcl-2 protein family is represented by both pro- and antiapoptotic members. Antiapoptotic proteins are often exploited by tumor cells to avoid their death, thus playing an important role in carcinogenesis and in acquisition of resistance to various therapeutic agents. Therefore, antiapoptotic proteins represent attractive targets for cancer therapy. A detailed investigation of interactions between Bcl-2 family proteins resulted in the development of highly selective inhibitors of individual antiapoptotic members. These agents are currently being actively studied at the preclinical and clinical stages and represent a promising therapeutic strategy, which is highlighted by approval of venetoclax, a selective inhibitor of Bcl-2, for medical use. Meanwhile, inhibition of antiapoptotic Bcl-2 family proteins has significant therapeutic potential that is yet to be revealed. In the coming era of precision medicine, a detailed study of the mechanisms responsible for the sensitivity or resistance of tumor cells to various therapeutic agents, as well as the search for the most effective combinations, is of great importance. Here, we discuss mechanisms of how the Bcl-2 family proteins function, principles of their inhibition by small molecules, success of this approach in cancer therapy, and, eventually, biochemical features that can be exploited to improve the use of Bcl-2 family inhibitors as anticancer drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

Abbreviations

AML:

acute myeloid leukemia

BH-domain:

Bcl-2 homology domain

CLL:

chronic lymphocytic leukemia

MM:

multiple myeloma

MOMP:

mitochondrial outer membrane permeabilization

NSCLC:

non-small cell lung carcinoma

OMM:

outer mitochondrial membrane

PCD:

programmed cell death

SCLC:

small-cell lung carcinoma

References

  1. Hanahan, D., and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation, Cell, 144, 646-674, doi: https://doi.org/10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  2. Dickens, L. S., Powley, I. R., Hughes, M. A., and MacFarlane, M. (2012) The “complexities” of life and death: death receptor signalling platforms, Exp. Cell Res., 318, 1269-1277, doi: https://doi.org/10.1016/j.yexcr.2012.04.005.

    Article  CAS  PubMed  Google Scholar 

  3. Czabotar, P. E., Lessene, G., Strasser, A., and Adams, J. M. (2013) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy, Nat. Rev. Mol. Cell Biol., 15, 49-63, doi: https://doi.org/10.1038/nrm3722.

    Article  CAS  Google Scholar 

  4. Senichkin, V. V., Streletskaia, A. Y., Zhivotovsky, B., and Kopeina, G. S. (2019) Molecular comprehension of Mcl-1: from gene structure to cancer therapy, Trends Cell Biol., 29, 549-562, doi: https://doi.org/10.1016/j.tcb.2019.03.004.

    Article  CAS  PubMed  Google Scholar 

  5. Wilson, W. H., O’Connor, O. A., Czuczman, M. S., LaCasce, A. S., Gerecitano, J. F., et al. (2010) Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity, Lancet Oncol., 11, 1149-1159, doi: https://doi.org/10.1016/S1470-2045(10)70261-8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Deeks, E. D. (2016) Venetoclax: first global approval, Drugs, 76, 979-987, doi: https://doi.org/10.1007/s40265-016-0596-x.

    Article  CAS  PubMed  Google Scholar 

  7. Westphal, D., Kluck, R. M., and Dewson, G. (2014) Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis, Cell Death Differ., 21, 196-205, doi: https://doi.org/10.1038/cdd.2013.139.

    Article  CAS  PubMed  Google Scholar 

  8. Kuwana, T., Bouchier-Hayes, L., Chipuk, J. E., Bonzon, C., Sullivan, B. A., Green, D. R., and Newmeyer, D. D. (2005) BH3 Domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly, Mol. Cell, 17, 525-535, doi: https://doi.org/10.1016/j.molcel.2005.02.003.

    Article  CAS  PubMed  Google Scholar 

  9. Czabotar, P. E., Westphal, D., Dewson, G., Ma, S., Hockings, C., et al. (2013) Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis, Cell, 152, 519-531, doi: https://doi.org/10.1016/j.cell.2012.12.031.

    Article  CAS  PubMed  Google Scholar 

  10. Cory, S., Roberts, A. W., Colman, P. M., and Adams, J. M. (2016) Targeting BCL-2-like proteins to kill cancer cells, Trends Cancer, 2, 443-460, doi: https://doi.org/10.1016/j.trecan.2016.07.001.

    Article  PubMed  Google Scholar 

  11. Singh, R., Letai, A., and Sarosiek, K. (2019) Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins, Nat. Rev. Mol. Cell Biol., 20, 175-193, doi: https://doi.org/10.1038/s41580-018-0089-8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Senichkin, V. V., Streletskaia, A. Y., Gorbunova, A. S., Zhivotovsky, B., and Kopeina, G. S. (2020) Saga of Mcl-1: regulation from transcription to degradation, Cell Death Differ., 27, 405-419, doi: https://doi.org/10.1038/s41418-019-0486-3.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Richter-Larrea, J. A., Robles, E. F., Fresquet, V., Beltran, E., Rullan, A. J., et al. (2010) Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma, Blood, 116, 2531-2542, doi: https://doi.org/10.1182/blood-2010-02-268003.

    Article  CAS  PubMed  Google Scholar 

  14. Tagawa, H., Karnan, S., Suzuki, R., Matsuo, K., Zhang, X., Ota, A., Morishima, Y., Nakamura, S., and Seto, M. (2005) Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM, Oncogene, 24, 1348-1358, doi: https://doi.org/10.1038/sj.onc.1208300.

    Article  CAS  PubMed  Google Scholar 

  15. Rampino, N., Yamamoto, H., Ionov, Y., Li, Y., Sawai, H., Reed, J. C., and Perucho, M. (1997) Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype, Science, 275, 967-969, doi: https://doi.org/10.1126/science.275.5302.967.

    Article  CAS  PubMed  Google Scholar 

  16. Yu, J., Yue, W., Wu, B., and Zhang, L. (2006) PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation, Clin. Cancer Res., 12, 2928-2936, doi: https://doi.org/10.1158/1078-0432.CCR-05-2429.

    Article  CAS  PubMed  Google Scholar 

  17. Sinicrope, F. A., Rego, R. L., Okumura, K., Foster, N. R., O’Connell, M. J., Sargent, D. J., and Windschitl, H. E. (2008) Prognostic impact of Bim, Puma, and Noxa expression in human colon carcinomas, Clin. Cancer Res., 14, 5810-5818, doi: https://doi.org/10.1158/1078-0432.CCR-07-5202.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., et al. (2010) The landscape of somatic copy-number alteration across human cancers, Nature, 463, 899-905, doi: https://doi.org/10.1038/nature08822.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Wesarg, E., Hoffarth, S., Wiewrodt, R., Kröll, M., Biesterfeld, S., Huber, C., and Schuler, M. (2007) Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer, Int. J. Cancer, 121, 2387-2394, doi: https://doi.org/10.1002/ijc.22977.

    Article  CAS  PubMed  Google Scholar 

  20. Faderl, S., Keating, M. J., Do, K. A., Liang, S. Y., Kantarjian, M., O’Brien, S., Garcia-Manero, G., Manshouri, T., and Albitar, M. (2002) Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL), Leukemia, 16, 1045-1052, doi: https://doi.org/10.1038/sj.leu.2402540.

    Article  CAS  PubMed  Google Scholar 

  21. Han, Y., Wu, N., Jiang, M., Chu, Y., Wang, Z., Liu, H., Cao, J., Liu, H., Xu, B., and Xie, X. (2019) Long non-coding RNA MYOSLID functions as a competing endogenous RNA to regulate MCL-1 expression by sponging miR-29c-3p in gastric cancer, Cell Prolif., 52, e12678, doi: https://doi.org/10.1111/cpr.12678.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Zhang, J., Wang, S., Wang, L., Wang, R., Chen, S., Pan, B., Sun, Y., and Chen, H. (2015) Prognostic value of Bcl-2 expression in patients with non-small-cell lung cancer: a meta-analysis and systemic review, Oncol. Targets Ther., 8, 3361-3369, doi: https://doi.org/10.2147/OTT.S89275.

    Article  Google Scholar 

  23. Henriksen, R., Wilander, E., and Löberg K. (1995) Expression and prognostic significance of Bcl-2 in ovarian tumours, Br. J. Cancer, 72, 1324-1329, doi: https://doi.org/10.1038/bjc.1995.509.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Chan, W. Y., Cheung, K. K., Schorge, J. O., Huang, L. W., Welch W. R. et al. (2000) Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers, Am. J. Pathol., 156, 409-417, doi: https://doi.org/10.1016/S0002-9440(10)64744-X.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nakano, T., Liu, D., Nakashima, N., Yokomise, H., Nii, K., et al. (2018) MCL-1 expression of non-small cell lung cancer as a prognostic factor and MCL-1 as a promising target for gene therapy, J. Clin. Oncol., 36, doi: https://doi.org/10.1200/jco.2018.36.15_suppl.e24236.

    Article  Google Scholar 

  26. Wu, X., Luo, Q., Zhao, P., Chang, W., Wang, Y., Shu, T., Ding, F., Li, B., and Liu, Z. (2019) MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer, Proc. Natl. Acad. Sci. USA, 116, 2961-2966, doi: https://doi.org/10.1073/pnas.1814742116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Williams, J., Lucas, P. C., Griffith, K. A., Choi, M., Fogoros, S., Hu, Y. Y., and Liu, J. R. (2005) Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease, Gynecol. Oncol., 96, 287-295, doi: https://doi.org/10.1016/j.ygyno.2004.10.026.

    Article  CAS  PubMed  Google Scholar 

  28. Reyna, D. E., Garner, T. P., Lopez, A., Kopp, F., Choudhary, G. S., et al. (2017) Direct activation of BAX by BTSA1 overcomes apoptosis resistance in acute myeloid leukemia, Cancer Cell, 32, 490-505, doi: https://doi.org/10.1016/j.ccell.2017.09.001.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Konopleva, M., Contractor, R., Tsao, T., Samudio, I., Ruvolo, P. P., Kitada, S., Deng, X., Zhai, D., and Shi, Y. X., et al. (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia, Cancer Cell, 10, 375-388, doi: https://doi.org/10.1016/j.ccr.2006.10.006.

    Article  CAS  PubMed  Google Scholar 

  30. Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., et al. (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets, Nat. Med., 19, 202-208, doi: https://doi.org/10.1038/nm.3048.

    Article  CAS  PubMed  Google Scholar 

  31. Arellano, M. L., Borthakur, G., Berger, M., Luer, J., and Raza, A. (2014) A phase II, multicenter, open-label study of obatoclax mesylate in patients with previously untreated myelodysplastic syndromes with anemia or thrombocytopenia, Clin. Lymphoma Myeloma Leuk., 14, 534-539, doi: https://doi.org/10.1016/j.clml.2014.04.007.

    Article  PubMed  Google Scholar 

  32. Tao, Z. F., Hasvold, L., Wang, L., Wang, X., Petros, A. M., et al. (2014) Discovery of a potent and selective BCL-XL inhibitor with in vivo activity, ACS Med. Chem. Lett., 5, 1088-1093, doi: https://doi.org/10.1021/ml5001867.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A. L., et al. (2016) The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models, Nature, 538, 477-482, doi: https://doi.org/10.1038/nature19830.

    Article  CAS  PubMed  Google Scholar 

  34. Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours, Nature, 435, 677-681, doi: https://doi.org/10.1038/nature03579.

    Article  CAS  PubMed  Google Scholar 

  35. Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., et al. (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor, Cancer Res., 68, 3421-3428, doi: https://doi.org/10.1158/0008-5472.CAN-07-5836.

    Article  CAS  PubMed  Google Scholar 

  36. Mérino, D., Khaw, S. L., Glaser, S. P., Anderson, D. J., Belmont, L. D., et al. (2012) Bcl-2, Bcl-x L, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells, Blood, 119, 5807-5816, doi: https://doi.org/10.1182/blood-2011-12-400929.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Roberts, A. W., Davids, M. S., Pagel, J. M., Kahl, B. S., Puvvada, S. D., et al. (2016) Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia, N. Engl. J. Med., 374, 311-322, doi: https://doi.org/10.1056/NEJMoa1513257.

    Article  CAS  PubMed  Google Scholar 

  38. Seymour, J. F., Kipps, T. J., Eichhorst, B., Hillmen, P., D’Rozario, J., et al. (2018) Venetoclax–Rituximab in relapsed or refractory chronic lymphocytic leukemia, N. Engl. J. Med., 378, 1107-1120, doi: https://doi.org/10.1056/NEJMoa1713976.

    Article  CAS  PubMed  Google Scholar 

  39. Casara, P., Davidson, J., Claperon, A., Toumelin-Braizat, G. L. Le, Vogler, M., et al. (2018) S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth, Oncotarget, 9, 20075-20088, doi: https://doi.org/10.18632/oncotarget.24744.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Mason, K. D., Carpinelli, M. R., Fletcher, J. I., Collinge, J. E., Hilton, A. A., et al. (2007) Programmed anuclear cell death delimits platelet life span, Cell, 128, 1173-1186, doi: https://doi.org/10.1016/j.cell.2007.01.037.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, X., Liu, X., Zhou, D., and Zheng, G. (2020) Targeting anti-apoptotic BCL-2 family proteins for cancer treatment, Future Med. Chem., 12, 563-565, doi: https://doi.org/10.4155/fmc-2020-0004.

    Article  CAS  PubMed  Google Scholar 

  42. Hartman, M. L., and Czyz, M. (2020) BCL-w: apoptotic and non-apoptotic role in health and disease, Cell Death Dis., 11, 260, doi: https://doi.org/10.1038/s41419-020-2417-0.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Lee, E. F., Dewson, G., Smith, B. J., Evangelista, M., Pettikiriarachchi, A., Dogovski, C., Perugini, M. A., Colman, P. M., and Fairlie, W. D. (2011) Crystal structure of a BCL-W domain-swapped dimer: Implications for the function of BCL-2 family proteins, Structure, 19, 1467-1476, doi: https://doi.org/10.1016/j.str.2011.07.015.

    Article  CAS  PubMed  Google Scholar 

  44. Harvey, E. P., Hauseman, Z. J., Cohen, D. T., Rettenmaier, T. J., Lee, S., et al. (2020) Identification of a covalent molecular inhibitor of anti-apoptotic BFL-1 by disulfide tethering, Cell Chem. Biol., 27, 647-656.e6, doi: https://doi.org/10.1016/j.chembiol.2020.04.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Czabotar, P. E., Lee, E. F., van Delft, M. F., Day, C. L., Smith, B. J., Huang, D. C. S., Fairlie, W. D., Hinds, M. G., and Colman, P. M. (2007) Structural insights into the degradation of Mcl-1 induced by BH3 domains, Proc. Natl. Acad. Sci. USA, 104, 6217-6222, doi: https://doi.org/10.1073/pnas.0701297104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pervushin, N. V., Senichkin, V. V., Zhivotovsky, B., and Kopeina, G. S. (2020) Mcl-1 as a “barrier” in cancer treatment: can we target it now? Intern. Rev. Cell Mol. Biol., 351, 23-55, doi: https://doi.org/10.1016/bs.ircmb.2020.01.002.

    Article  Google Scholar 

  47. Tron, A. E., Belmonte, M. A., Adam, A., Aquila, B. M., Boise, L. H., et al. (2018) Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia, Nat. Commun., 9, 5341, doi: https://doi.org/10.1038/s41467-018-07551-w.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Caenepeel, S., Brown, S. P., Belmontes, B., Moody, G., Keegan, K. S., Chui, D., et al. (2018) AMG 176, a selective MCL1 inhibitor, is effective in hematological cancer models alone and in combination with established therapies, Cancer Discov., 8, 1582-1597, doi: https://doi.org/10.1158/2159-8290.CD-18-0387.

    Article  CAS  PubMed  Google Scholar 

  49. Montero, J., and Letai, A. (2018) Why do BCL-2 inhibitorswork and where should we use them in the clinic? Cell Death Differ., 25, 56-64, doi: https://doi.org/10.1038/cdd.2017.183.

    Article  CAS  PubMed  Google Scholar 

  50. Certo, M., Moore, V. D. G., Nishino, M., Wei, G., Korsmeyer, S., Armstrong, S. A., and Letai, A. (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members, Cancer Cell, 9, 351-365, doi: https://doi.org/10.1016/j.ccr.2006.03.027.

    Article  CAS  PubMed  Google Scholar 

  51. Sarosiek, K. A., Fraser, C., Muthalagu, N., Bhola, P. D., Chang, W., et al. (2017) Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics, Cancer Cell, 31, 142-156, doi: https://doi.org/10.1016/j.ccell.2016.11.011.

    Article  CAS  PubMed  Google Scholar 

  52. Xiang, Z., Luo, H., Payton, J. E., Cain, J., Ley, T. J., Opferman, J. T., and Tomasson, M. H. (2010) Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia, J. Clin. Invest., 120, 2109-2118, doi: https://doi.org/10.1172/JCI39964.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Moore, V. D. G., Brown, J. R., Certo, M., Love, T. M., Novina, C. D., and Letai, A. (2007) Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737, J. Clin. Invest., 117, 112-121, doi: https://doi.org/10.1172/JCI28281.

    Article  CAS  Google Scholar 

  54. Pan, R., Hogdal, L. J., Benito, J. M., Bucci, D., Han, L., et al. (2014) Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia, Cancer Discov., 4, 362-675, doi: https://doi.org/10.1158/2159-8290.CD-13-0609.

    Article  CAS  PubMed  Google Scholar 

  55. Kumar, S., Kaufman, J. L., Gasparetto, C., Mikhael, J., Vij, R., et al. (2017) Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma, Blood, 130, 2401-2409, doi: https://doi.org/10.1182/blood-2017-06-788786.

    Article  CAS  PubMed  Google Scholar 

  56. Davids, M. S., Roberts, A. W., Seymour, J. F., Pagel, J. M., Kahl, B. S., et al. (2017) Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma, J. Clin. Oncol., 35, 826-833, doi: https://doi.org/10.1200/JCO.2016.70.4320.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Moujalled, D. M., Pomilio, G., Ghiurau, C., Ivey, A., Salmon, J., et al. (2019) Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia, Leukemia, 33, 905-917, doi: https://doi.org/10.1038/s41375-018-0261-3.

    Article  CAS  PubMed  Google Scholar 

  58. Zinzani, P. L., Topp, M. S., Yuen, S. L., Rusconi, C., Fleury, I., et al. (2016) Phase 2 study of venetoclax plus rituximab or randomized ven plus bendamustine+rituximab (BR) versus BR in patients with relapsed/refractory follicular lymphoma: interim data, Blood, 128, 617-617, doi: https://doi.org/10.1182/blood.v128.22.617.617.

    Article  Google Scholar 

  59. Moreau, P., Chanan-Khan, A., Roberts, A. W., Agarwal, A. B., Facon, T., et al. (2017) Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM, Blood, 130, 2392-2400, doi: https://doi.org/10.1182/blood-2017-06-788323.

    Article  CAS  PubMed  Google Scholar 

  60. Touzeau, C., Ryan, J., Guerriero, J., Moreau, P., Chonghaile, T. N., Gouill, S. Le, Richardson, P., Anderson, K., Amiot, M., and Letai, A. (2016) BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics, Leukemia, 30, 761-764, doi: https://doi.org/10.1038/leu.2015.184.

    Article  CAS  PubMed  Google Scholar 

  61. Spencer, A., Rosenberg, A. S., Jakubowiak, A., Raje, N., Chatterjee, M., et al. (2019) A phase 1, first-in-human study of AMG 176, a selective MCL-1 inhibitor, in patients with relapsed or refractory multiple myeloma, Clin. Lymphoma Myeloma Leuk., 19, 53-54, doi: https://doi.org/10.1016/j.clml.2019.09.081.

    Article  Google Scholar 

  62. Konopleva, M., Pollyea, D. A., Potluri, J., Chyla, B., Hogdal, L., et al. (2016) Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia, Cancer Discov., 6, 1106-1117, doi: https://doi.org/10.1158/2159-8290.CD-16-0313.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Lochmann, T. L., Floros, K. V., Naseri, M., Powell, K. M., Cook, W., et al. (2018) Venetoclax is effective in small-cell lung cancers with high BCL-2 expression, Clin. Cancer Res., 24, 360-369, doi: https://doi.org/10.1158/1078-0432.CCR-17-1606.

    Article  CAS  PubMed  Google Scholar 

  64. Wong, K. Y., and Chim, C. S. (2020) Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma, J. Pharm. Pharmacol., 72, 728-737, doi: https://doi.org/10.1111/jphp.13240.

    Article  CAS  PubMed  Google Scholar 

  65. Yasuda, Y., Ozasa, H., Kim, Y. H., Yamazoe, M., Ajimizu, H., et al. (2020) MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression, Cell Death Dis., 11, 1-15, doi: https://doi.org/10.1038/s41419-020-2379-2.

    Article  CAS  Google Scholar 

  66. Khaw, S. L., Mérino, D., Anderson, M. A., Glaser, S. P., Bouillet, P., Roberts, A. W., and Huang, D. C. S. (2014) Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199, Leukemia, 28, 1207-1215, doi: https://doi.org/10.1038/leu.2014.1.

    Article  CAS  PubMed  Google Scholar 

  67. Pham, L. V., Huang, S., Zhang, H., Zhang, J., Bell, T., et al. (2018) Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas, Clin. Cancer Res., 24, 3967-3980, doi: https://doi.org/10.1158/1078-0432.CCR-17-3004.

    Article  CAS  PubMed  Google Scholar 

  68. Bodo, J., Zhao, X., Durkin, L., Souers, A. J., Phillips, D. C., Smith, M. R., and His, E. D. (2016) Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells, Oncotarget, 7, 70000-70010, doi: https://doi.org/10.18632/oncotarget.12132.

    Article  PubMed Central  PubMed  Google Scholar 

  69. Kontro, M., Kumar, A., Majumder, M. M., Eldfors, S., Parsons, A., et al. (2017) HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia, Leukemia, 31, 301-309, doi: https://doi.org/10.1038/leu.2016.222.

    Article  CAS  PubMed  Google Scholar 

  70. Avet-Loiseau, H., Attal, M., Moreau, P., Charbonnel, C., Garban, F., et al. (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome, Blood, 109, 3489-3495, doi: https://doi.org/10.1182/blood-2006-08-040410.

    Article  CAS  PubMed  Google Scholar 

  71. Touzeau, C., Dousset, C., Gouill, S. Le, Sampath, D., Leverson, J. D., Souers, A. J., Maïga, S., Béné, M. C., Moreau, P., Pellat-Deceunynck, C., and Amiot, M. (2014) The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma, Leukemia, 28, 210-212, doi: https://doi.org/10.1038/leu.2013.216.

    Article  CAS  PubMed  Google Scholar 

  72. Chan, S. M., Thomas, D., Corces-Zimmerman, M. R., Xavy, S., Rastogi, S., Hong, W. J., Zhao, F., Medeiros, B. C., Tyvoll, D. A., and Majeti, R. (2015) Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia, Nat. Med., 21, 178-184, doi: https://doi.org/10.1038/nm.3788.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Blombery, P., Thompson, E. R., Nguyen, T., Birkinshaw, R. W., Gong, J. N., et al. (2020) Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax, Blood, 135, 773-777, doi: https://doi.org/10.1182/blood.2019004205.

    Article  PubMed Central  PubMed  Google Scholar 

  74. Tahir, S. K., Smith, M. L., Hessler, P., Rapp, L. R., Idler, K. B., Park, C. H., Leverson, J. D., and Lam, L. T. (2017) Potential mechanisms of resistance to venetoclax and strategies to circumvent it, BMC Cancer, 17, 399, doi: https://doi.org/10.1186/s12885-017-3383-5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Mazumder, S., Choudhary, G. S., Al-Harbi, S., and Almasan, A. (2012) Mcl-1 phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells, Cancer Res., 72, 3069-3079, doi: https://doi.org/10.1158/0008-5472.CAN-11-4106.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Konopleva, M., Milella, M., Ruvolo, P., Watts, J. C., Ricciardi, M. R., et al. (2012) MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex, Leukemia, 26, 778-787, doi: https://doi.org/10.1038/leu.2011.287.

    Article  CAS  PubMed  Google Scholar 

  77. Choudhary, G. S., Al-Harbi, S., Mazumder, S., Hill, B. T., Smith, M. R., Bodo, J., His, E. D., and Almasan, A. (2015) MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies, Cell Death Dis., 6, 1593, doi: https://doi.org/10.1038/cddis.2014.525.

    Article  CAS  Google Scholar 

  78. Fresquet, V., Rieger, M., Carolis, C., García-Barchino, M. J., and Martinez-Climent, J. A. (2014) Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma, Blood, 123, 4111-4119, doi: https://doi.org/10.1182/blood-2014-03-560284.

    Article  CAS  PubMed  Google Scholar 

  79. Blombery, P., Anderson, M. A., Gong, J. N., Thijssen, R., Birkinshaw, R. W., et al. (2019) Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia, Cancer Discov., 9, 342-353, doi: https://doi.org/10.1158/2159-8290.CD-18-1119.

    Article  CAS  PubMed  Google Scholar 

  80. Tausch, E., Close, W., Dolnik, A., Bloehdorn, J., Chyla, B., Bullinger, L., Döhner, H., Mertens, D., and Stilgenbauer, S. (2019) Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia, Haematologica, 104, 434-437, doi: https://doi.org/10.3324/haematol.2019.222588.

    Article  CAS  Google Scholar 

  81. Ramsey, H. E., Fischer, M. A., Lee, T., Gorska, A. E., Arrate, M. P., et al. (2018) A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia, Cancer Discov., 8, 1566-1581, doi: https://doi.org/10.1158/2159-8290.CD-18-0140.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Lee, E. F., Harris, T. J., Tran, S., Evangelista, M., Arulananda, S., et al. (2019) BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival, Cell Death Dis., 10, 1-14, doi: https://doi.org/10.1038/s41419-019-1568-3.

    Article  CAS  Google Scholar 

  83. Khaw, S. L., Suryani, S., Evans, K., Richmond, J., Robbins, A., et al. (2016) Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia, Blood, 128, 1382-1395, doi: https://doi.org/10.1182/blood-2016-03-707414.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Weeden, C. E., Ah-Cann, C., Holik, A. Z., Pasquet, J., Garnier, J. M., Merino, D., Lessene, G., and Asselin-Labat, M. L. (2018) Dual inhibition of BCL-XL and MCL-1 is required to induce tumour regression in lung squamous cell carcinomas sensitive to FGFR inhibition, Oncogene, 37, 4475-4488, doi: https://doi.org/10.1038/s41388-018-0268-2.

    Article  CAS  PubMed  Google Scholar 

  85. Debrincat, M. A., Josefsson, E. C., James, C., Henley, K. J., Ellis, S., et al. (2012) Mcl-1 and Bcl-x L coordinately regulate megakaryocyte survival, Blood, 119, 5850-5858, doi: https://doi.org/10.1182/blood-2011-12-398834.

    Article  CAS  PubMed  Google Scholar 

  86. Chen, J., Jin, S., Abraham, V., Huang, X., Liu, B., Mitten, M. J., et al. (2011) The Bcl-2/Bcl-X L/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivo, Mol. Cancer Ther., 10, 2340-2349, doi: https://doi.org/10.1158/1535-7163.MCT-11-0415.

    Article  CAS  PubMed  Google Scholar 

  87. Corcoran, R. B., Cheng, K. A., Hata, A. N., Faber, A. C., Ebi, H., et al. (2013) Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models, Cancer Cell, 23, 121-128, doi: https://doi.org/10.1016/j.ccr.2012.11.007.

    Article  CAS  PubMed  Google Scholar 

  88. Luedtke, D. A., Su, Y., Liu, S., Edwards, H., Wang, Y., Lin, H., Taub, J. W., and Ge, Y. (2018) Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1, J. Cell. Mol. Med., 22, 6099-6111, doi: https://doi.org/10.1111/jcmm.13886.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Luedtke, D. A., Su, Y., Ma, J., Li, X., Buck, S. A., et al. (2020) Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemi, Signal. Transduct. Target. Ther., 5, 1-11, doi: https://doi.org/10.1038/s41392-020-0112-3.

    Article  CAS  Google Scholar 

  90. Cidado, J., Boiko, S., Proia, T., Ferguson, D., Criscione, S. W., et al. (2020) AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematologic cancer cells, Clin. Cancer Res., 26, 922-934, doi: https://doi.org/10.1158/1078-0432.CCR-19-1853.

    Article  CAS  PubMed  Google Scholar 

  91. Patel, V. M., Balakrishnan, K., Douglas, M., Tibbitts, T., Xu, E. Y., et al. (2017) Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199), Leukemia, 31, 1872-1881, doi: https://doi.org/10.1038/leu.2016.382.

    Article  CAS  PubMed  Google Scholar 

  92. Matulis, S. M., Gupta, V. A., Nooka, A. K., Hollen, H. V., Kaufman, J. L., Lonial, S., and Boise, L. H. (2016) Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax, Leukemia, 30, 1086-1093, doi: https://doi.org/10.1038/leu.2015.350.

    Article  CAS  PubMed  Google Scholar 

  93. The, T. C., Nguyen, N. Y., Moujalled, D. M., Segal, D., Pomilio, G., et al. (2018) Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1, Leukemia, 32, 303-312, doi: https://doi.org/10.1038/leu.2017.243.

    Article  CAS  Google Scholar 

  94. Mali, R. S., Zhang, Q., DeFilippis, R., Cavazos, A., Kuruvilla, V. M., et al. (2020) Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models, Haematologica, 244020, doi: https://doi.org/10.3324/haematol.2019.244020.

  95. Cathelin, S., Sharon, D., Subedi, A., Cojocari, D., Phillips, D. C., et al. (2018) Combination of enasidenib and venetoclax shows superior anti-leukemic activity against IDH2 mutated AML in patient-derived xenograft models, Blood, 132, 562-562, doi: https://doi.org/10.1182/blood-2018-99-119688.

    Article  Google Scholar 

  96. Koch, R., Christie, A. L., Crombie, J. L., Palmer, A. C., Plana, D., et al. (2019) Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas, Blood, 133, 566-575, doi: https://doi.org/10.1182/blood-2018-07-865527.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Nangia, V., Siddiqui, F. M., Caenepeel, S., Timonina, D., Bilton, S. J., et al. (2018) Exploiting MCL1 dependency with combination MEK + MCL1 inhibitors leads to induction of apoptosis and tumor regression in KRAS-Mutant non-small cell lung cancer, Cancer Discov., 8, 1598-1613, doi: https://doi.org/10.1158/2159-8290.CD-18-0277.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Merino, D., Whittle, J. R., Vaillant, F., Serrano, A., Gong, J. N., et al. (2017) 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., 9, 401, doi: https://doi.org/10.1126/scitranslmed.aam7049.

    Article  CAS  Google Scholar 

  99. Leverson, J. D., Phillips, D. C., Mitten, M. J., Boghaert, E. R., Diaz, D., et al. (2015) Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy, Sci. Transl. Med., 7, doi: https://doi.org/10.1126/scitranslmed.aaa4642.

    Article  Google Scholar 

  100. Shoemaker, A. R., Oleksijew, A., Bauch, J., Belli, B. A., Borre, T., et al. (2006) A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo, Cancer Res., 66, 8731-8739, doi: https://doi.org/10.1158/0008-5472.CAN-06-0367.

    Article  CAS  PubMed  Google Scholar 

  101. DiNardo, C. D., Pratz, K., Pullarkat, V., Jonas, B. A., Arellano, M., et al. (2019) Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia, Blood, 133, 7-17, doi: https://doi.org/10.1182/blood-2018-08-868752.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Jin, S., Cojocari, D., Purkal, J. J., Popovic, R., Talaty, N. N., et al. (2020) 5-Azacitidine induces NOXA to prime AML cells for venetoclax-mediated apoptosis, Clin. Cancer Res., 26, 3371-3383 doi: https://doi.org/10.1158/1078-0432.ccr-19-1900.

    Article  CAS  PubMed  Google Scholar 

  103. Pollyea, D. A., Stevens, B. M., Jones, C. L., Winters, A., Pei, S., et al. (2018) Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia, Nat. Med., 24, 1859-1866, doi: https://doi.org/10.1038/s41591-018-0233-1.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Jain, N., Keating, M., Thompson, P., Ferrajoli, A., Burger, J., et al. (2019) Ibrutinib and venetoclax for first-line treatment of CLL, N. Engl. J. Med., 380, 2095-2103, doi: https://doi.org/10.1056/NEJMoa1900574.

    Article  CAS  PubMed  Google Scholar 

  105. Tam, C. S., Anderson, M. A., Pott, C., Agarwal, R., Handunnetti, S., et al. (2018) Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma, N. Engl. J. Med., 378, 1211-1223, doi: https://doi.org/10.1056/NEJMoa1715519.

    Article  CAS  PubMed  Google Scholar 

  106. Cervantes-Gomez, F., Lamothe, B., Woyach, J. A., Wierda, W. G., Keating, M. J., Balakrishnan, K., and Gandhi, V. (2015) Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia, Clin. Cancer Res., 21, 3705-3715, doi: https://doi.org/10.1158/1078-0432.CCR-14-2809.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Russian Science Foundation (project no. 17-75-20102). The work in the authors’ laboratories is also supported by the Russian Foundation for Basic Research (project no. 20-015-00500), the Swedish (project no. 190345) and Stockholm (project no. 181301) Cancer Societies.

Author information

Authors and Affiliations

  1. Faculty of Basic Medicine, Lomonosov Moscow State University, 119192, Moscow, Russia

    V. V. Senichkin, N. V. Pervushin, A. P. Zuev, B. Zhivotovsky & G. S. Kopeina

  2. Institute of Environmental Medicine, Karolinska Institute, 17177, Stockholm, Sweden

    B. Zhivotovsky

Authors
  1. V. V. Senichkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. V. Pervushin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. P. Zuev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Zhivotovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. S. Kopeina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. S. Kopeina.

Ethics declarations

The authors declare no conflict of interests. This article does not contain any studies involving human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Senichkin, V.V., Pervushin, N.V., Zuev, A.P. et al. Targeting Bcl-2 Family Proteins: What, Where, When?. Biochemistry Moscow 85, 1210–1226 (2020). https://doi.org/10.1134/S0006297920100090

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920100090

Keywords

Search

Navigation