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The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs

Nature Reviews Cancer volume 22, pages 45–64 (2022)Cite this article

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Abstract

Apoptosis is a form of programmed cell death that is regulated by the balance between prosurvival and proapoptotic BCL-2 protein family members. Evasion of apoptosis is a hallmark of cancer that arises when this balance is tipped in favour of survival. One form of anticancer therapeutic, termed ‘BH3-mimetic drugs’, has been developed to directly activate the apoptosis machinery in malignant cells. These drugs bind to and inhibit specific prosurvival BCL-2 family proteins, thereby mimicking their interaction with the BH3 domains of proapoptotic BCL-2 family proteins. The BCL-2-specific inhibitor venetoclax is approved by the US Food and Drug Administration and many regulatory authorities worldwide for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia. BH3-mimetic drugs targeting other BCL-2 prosurvival proteins have been tested in preclinical models of cancer, and drugs targeting MCL-1 or BCL-XL have advanced into phase I clinical trials for certain cancers. As with all therapeutics, efficacy and tolerability need to be carefully balanced to achieve a therapeutic window whereby there is significant anticancer activity with an acceptable safety profile. In this Review, we outline the current state of BH3-mimetic drugs targeting various prosurvival BCL-2 family proteins and discuss emerging data regarding primary and acquired resistance to these agents and approaches that may overcome this. We highlight issues that need to be addressed to further advance the clinical application of BH3-mimetic drugs, both alone and in combination with additional anticancer agents (for example, standard chemotherapeutic drugs or inhibitors of oncogenic kinases), for improved responses in patients with cancer.

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Fig. 1: The cell-intrinsic (BCL-2 regulated) apoptosis pathway, indicating where BH3-mimetic drugs act to induce apoptosis.
Fig. 2: Binding mode of select BH3-mimetic compounds in complex with prosurvival proteins.

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References

  1. Strasser, A., O’Connor, L. & Dixit, V. M. Apoptosis signaling. Annu. Rev. Biochem. 69, 217–245 (2000).

    CAS  PubMed  Google Scholar 

  2. Green, D. R. The coming decade of cell death research: five riddles. Cell 177, 1094–1107 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Czabotar, P. E., Lessene, G., Strasser, A. & Adams, J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49–63 (2014).

    CAS  PubMed  Google Scholar 

  4. Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20, 175–193 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Czabotar, P. E. et al. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 152, 519–531 (2013).

    CAS  PubMed  Google Scholar 

  6. Dewson, G. et al. Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Mol. Cell 36, 696–703 (2009).

    CAS  PubMed  Google Scholar 

  7. Brouwer, J. M. et al. Bak core and latch domains separate during activation, and freed core domains form symmetric homodimers. Mol. Cell 55, 938–946 (2014).

    CAS  PubMed  Google Scholar 

  8. Bleicken, S. et al. Structural model of active Bax at the membrane. Mol. Cell 56, 496–505 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Aluvila, S. et al. Organization of the mitochondrial apoptotic BAK pore: oligomerization of the BAK homodimers. J. Biol. Chem. 289, 2537–2551 (2014).

    CAS  PubMed  Google Scholar 

  10. Cowan, A. D. et al. BAK core dimers bind lipids and can be bridged by them. Nat. Struct. Mol. Biol. 27, 1024–1031 (2020).

    CAS  PubMed  Google Scholar 

  11. Birkinshaw, R. W. et al. Structure of detergent-activated BAK dimers derived from the inert monomer. Mol. Cell 81, 2123–2134 e2125 (2021).

    CAS  PubMed  Google Scholar 

  12. Happo, L., Strasser, A. & Cory, S. BH3-only proteins in apoptosis at a glance. J. Cell Sci. 125, 1081–1087 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen, L. et al. Differential targeting of pro-survival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17, 393–403 (2005).

    CAS  PubMed  Google Scholar 

  14. Kuwana, T. et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol. Cell 17, 525–535 (2005).

    CAS  PubMed  Google Scholar 

  15. Opferman, J. T. et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426, 671–676 (2003).

    CAS  PubMed  Google Scholar 

  16. Merino, D. et al. BH3-mimetic drugs: blazing the trail for new cancer medicines. Cancer Cell 34, 879–891 (2018).

    CAS  PubMed  Google Scholar 

  17. Sarosiek, K. A. & Letai, A. Directly targeting the mitochondrial pathway of apoptosis for cancer therapy with BH3 mimetics: recent successes, current challenges and future promise. FEBS J. 283, 3523–3533 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Opferman, J. et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307, 1101–1104 (2005).

    CAS  PubMed  Google Scholar 

  19. Wang, X. et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev. 27, 1351–1364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Thomas, R. L. et al. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev. 27, 1365–1377 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kotschy, A. et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538, 477–482 (2016). This study provides the first public disclosure of a specific and potent MCL-1-targeting BH3-mimetic compound and a description of its impact in preclinical tumour models in vitro and in vivo.

    PubMed  Google Scholar 

  22. Brinkmann, K. et al. The combination of reduced MCL-1 and standard chemotherapeutics is tolerable in mice. Cell Death Differ. 24, 2032–2043 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsujimoto, Y. & Croce, C. M. Recent progress on the human bcl-2 gene involved in follicular lymphoma: characterization of the protein products. Curr. Top. Microbiol. Immunol. 141, 337–340 (1988).

    CAS  PubMed  Google Scholar 

  24. Tsujimoto, Y., Gorham, J., Cossman, J., Jaffe, E. & Croce, C. M. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229, 1390–1393 (1985).

    CAS  PubMed  Google Scholar 

  25. Robertson, L. E., Plunkett, W., McConnell, K., Keating, M. J. & McDonnell, T. J. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 10, 456–459 (1996).

    CAS  PubMed  Google Scholar 

  26. Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005). This study reports the first BH3-mimetic compound (inhibiting BCL-2, BCL-XL and BCL-W) and a description of its impact in preclinical tumour models in vitro and in vivo.

    CAS  PubMed  Google Scholar 

  27. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013). This study provides the first description of a BCL-2-specific BH3-mimetic drug used in the clinic to treat patients with CLL.

    CAS  PubMed  Google Scholar 

  28. Konopleva, M. et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375–388 (2006).

    CAS  PubMed  Google Scholar 

  29. Pan, R. et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 4, 362–375 (2014).

    CAS  PubMed  Google Scholar 

  30. Touzeau, C. et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia 28, 210–212 (2014).

    CAS  PubMed  Google Scholar 

  31. Diepstraten, S. T. et al. BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines. Blood Adv. 4, 356–366 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Adams, C. M. et al. BCL-W has a fundamental role in B cell survival and lymphomagenesis. J. Clin. Invest. 127, 635–650 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. Adams, C. M. et al. Targeting BCL-W and BCL-XL as a therapeutic strategy for Hodgkin lymphoma. Leukemia 34, 947–952 (2020).

    PubMed  Google Scholar 

  34. Vaillant, F. et al. Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 24, 120–129 (2013). This study provides a rationale for use of BH3-mimetic drugs targeting BCL-2 in ER-positive breast cancer alongside use of standard-of-care drugs.

    CAS  PubMed  Google Scholar 

  35. Lochmann, T. L. et al. Venetoclax is effective in small-cell lung cancers with high BCL-2 expression. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-1606 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Casara, P. et al. S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth. Oncotarget 9, 20075–20088 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Caenepeel, S. et al. AMG 176, a Selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov. 8, 1582–1597 (2018).

    CAS  PubMed  Google Scholar 

  38. Tron, A. E. et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun. 9, 5341 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Grundy, M., Balakrishnan, S., Fox, M., Seedhouse, C. H. & Russell, N. H. Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells. Oncotarget 9, 37777–37789 (2018).

    PubMed  PubMed Central  Google Scholar 

  40. Hormi, M. et al. Pairing MCL-1 inhibition with venetoclax improves therapeutic efficiency of BH3-mimetics in AML. Eur. J. Haematol. 105, 588–596 (2020).

    CAS  PubMed  Google Scholar 

  41. Luedtke, D. A. et al. Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal. Transduct. Target. Ther. 2, 17012 (2017).

    PubMed  PubMed Central  Google Scholar 

  42. Moujalled, D. M. et al. 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 (2019). This study provides evidence that co-targeting of BCL-2 and MCL-1 would be efficacious for therapy for patients with AML.

    CAS  PubMed  Google Scholar 

  43. Moujalled, D. M. et al. Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. Blood Adv. 4, 2762–2767 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Seyfried, F. et al. Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling. Cell Death Dis. 10, 571 (2019).

    PubMed  PubMed Central  Google Scholar 

  45. Brennan, M. S. et al. Humanized Mcl-1 mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use. Blood 132, 1573–1583 (2018).

    CAS  PubMed  Google Scholar 

  46. Sejic, N. et al. BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK-cell lymphoma. Blood Adv. 4, 4775–4787 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Punnoose, E. A. et al. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol. Cancer Ther. 15, 1132–1144 (2016).

    CAS  PubMed  Google Scholar 

  48. Gong, J. N. et al. Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood 128, 1834–1844 (2016).

    CAS  PubMed  Google Scholar 

  49. Vogler, M. et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 113, 4403–4413 (2009).

    CAS  PubMed  Google Scholar 

  50. Dengler, M. A. et al. Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma. Oncogene 39, 2009–2023 (2020).

    CAS  PubMed  Google Scholar 

  51. Tromp, J. M. et al. Dichotomy in NF-kappaB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering. Oncogene 29, 5071–5082 (2010).

    CAS  PubMed  Google Scholar 

  52. Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173–1186 (2007). This study provides evidence that BH3-mimetic drugs targeting BCL-XL would cause on-target thrombocytopenia, which has ultimately hampered their clinical application.

    CAS  PubMed  Google Scholar 

  53. Soderquist, R. S. et al. Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity. Nat. Commun. 9, 3513 (2018). This study outlines screening approaches to predict the effectiveness of combinations of BH3-mimetic drugs targeting different prosurvival BCL-2 family proteins in diverse types of cancer cell.

    PubMed  PubMed Central  Google Scholar 

  54. Abdul Rahman, S. F. et al. Co-inhibition of BCL-XL and MCL-1 with selective BCL-2 family inhibitors enhances cytotoxicity of cervical cancer cell lines. Biochem. Biophys. Rep. 22, 100756 (2020).

    PubMed  PubMed Central  Google Scholar 

  55. Kehr, S. et al. Targeting BCL-2 proteins in pediatric cancer: dual inhibition of BCL-XL and MCL-1 leads to rapid induction of intrinsic apoptosis. Cancer Lett. 482, 19–32 (2020).

    CAS  PubMed  Google Scholar 

  56. Lee, E. F. et al. BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival. Cell Death Dis. 10, 342 (2019).

    PubMed  PubMed Central  Google Scholar 

  57. Weeden, C. E. et al. 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 (2018).

    CAS  PubMed  Google Scholar 

  58. Ow, T. J. et al. Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1. Oncotarget 10, 494–510 (2019).

    PubMed  PubMed Central  Google Scholar 

  59. Arulananda, S. et al. BCL-XL is an actionable target for treatment of malignant pleural mesothelioma. Cell Death Discov. 6, 114 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Luo, M.-J. et al. Defining the susceptibility of colorectal cancers to BH3-mimetic compounds. Cell Death Dis. 11, 735 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Lian, B. S. X. et al. Synergistic anti-proliferative effects of combination of ABT-263 and MCL-1 selective inhibitor A-1210477 on cervical cancer cell lines. BMC Res. Notes 11, 197 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Hikita, H. et al. Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. Hepatology 50, 1217–1226 (2009).

    CAS  PubMed  Google Scholar 

  63. Khan, S. et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25, 1938–1947 (2019). This study provides evidence that BCL-XL degraders or inhibitors can effectively kill tumour cells, while not impacting platelet survival.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang, X. et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL. Chem. Commun. 55, 14765–14768 (2019).

    CAS  Google Scholar 

  65. Zall, H., Weber, A., Besch, R., Zantl, N. & Hacker, G. Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1. Mol. Cancer 9, 164 (2010).

    PubMed  PubMed Central  Google Scholar 

  66. Bean, G. R. et al. PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci. Signal. 6, ra20 (2013).

    PubMed  PubMed Central  Google Scholar 

  67. Zhu, R. et al. FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation. Signal. Transduct. Target. Ther. 6, 186 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Merino, D. et al. 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. https://doi.org/10.1126/scitranslmed.aam7049 (2017).

    Article  PubMed  Google Scholar 

  69. Gayle, S. S. et al. Targeting BCL-xL improves the efficacy of bromodomain and extra-terminal protein inhibitors in triple-negative breast cancer by eliciting the death of senescent cells. J. Biol. Chem. 294, 875–886 (2019).

    CAS  PubMed  Google Scholar 

  70. Sarif, Z., Tolksdorf, B., Fechner, H. & Eberle, J. Mcl-1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cells. Mol. Carcinog. 59, 1256–1268 (2020).

    CAS  PubMed  Google Scholar 

  71. Cummin, T. E. C. et al. BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression. Blood Adv. 4, 3316–3328 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Roberts, A. W. et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 311–322 (2016). This article reports the phase I dose escalation of venetoclax in patients with relapsed CLL, showing it could be administered safely and achieve substantial reductions in tumour burden.

    CAS  PubMed  Google Scholar 

  73. Otto, T. & Sicinski, P. Cell cycle proteins as promising targets in cancer therapy. Nat. Rev. Cancer 17, 93–115 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Nangia, V. et al. 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 (2018). This study provides a rationale for the clinical evaluation of MEK inhibitors in combination with MCL-1 inhibitors for the treatment of KRAS-mutant NSCLC.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cragg, M. S., Kuroda, J., Puthalakath, H., Huang, D. C. S. & Strasser, A. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires Bim and can be enhanced by BH3 mimetics. PLoS Med. 4, 1681–1689 (2007).

    CAS  PubMed  Google Scholar 

  76. Cragg, M. S., Jansen, E. S., Cook, M., Strasser, A. & Scott, C. L. Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J. Clin. Invest. 118, 3651–3659 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Ommer, J. et al. Aurora a kinase inhibition destabilizes PAX3-FOXO1 and MYCN and synergizes with navitoclax to induce rhabdomyosarcoma cell death. Cancer Res. 80, 832–842 (2020).

    CAS  PubMed  Google Scholar 

  78. Fan, W. et al. MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents. Cancer Res. 71, 4494–4505 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Luo, Q. et al. A Novel BCL-2 inhibitor APG-2575 exerts synthetic lethality with BTK or MDM2-p53 inhibitor in diffuse large B-cell lymphoma. Oncol. Res. 28, 331–344 (2020).

    PubMed  PubMed Central  Google Scholar 

  80. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03537482 (2018).

  81. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04215809 (2020).

  82. Ball, B. J. et al. Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure. Blood Adv. 4, 2866–2870 (2020).

    PubMed  PubMed Central  Google Scholar 

  83. Tsao, T. et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann. Hematol. 91, 1861–1870 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Cojocari, D. et al. Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia. Haematologica https://doi.org/10.3324/haematol.2020.272609 (2021).

    Article  PubMed Central  Google Scholar 

  85. Parker, J. E. et al. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood 96, 3932–3938 (2000).

    CAS  PubMed  Google Scholar 

  86. Bogenberger, J. M. et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk. Lymphoma 56, 226–229 (2015).

    PubMed  Google Scholar 

  87. Jilg, S. et al. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients. Leukemia 30, 112–123 (2016).

    CAS  PubMed  Google Scholar 

  88. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).

    CAS  PubMed  Google Scholar 

  89. Wilson, W. H. et al. 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 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Roberts, A. W. et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J. Clin. Oncol. 30, 488–496 (2012).

    CAS  PubMed  Google Scholar 

  91. Roberts, A. W. et al. Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+lymphoid malignancies. Br. J. Haematol. 170, 669–678 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kipps, T. J. et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk. Lymphoma 56, 2826–2833 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhang, H. et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 14, 943–951 (2007).

    CAS  PubMed  Google Scholar 

  94. Anderson, M. A. et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 127, 3215–3224 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Le Gouill, S. et al. A new BCL-2 inhibitor (S55746/BCL201) as monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: preliminary results of the first-in-human study. Hematol. Oncol. 35, 47–48 (2017).

    Google Scholar 

  96. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03755154 (2018).

  97. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02920697 (2016).

  98. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02920541 (2016).

  99. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04742101 (2021).

  100. Stilgenbauer, S. et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 17, 768–778 (2016).

    CAS  PubMed  Google Scholar 

  101. Seymour, J. F. Effective mitigation of tumor lysis syndrome with gradual venetoclax dose ramp, prophylaxis, and monitoring in patients with chronic lymphocytic leukemia. Ann. Hematol. 95, 1361–1362 (2016).

    PubMed  Google Scholar 

  102. Gribben, J. G. Practical management of tumour lysis syndrome in venetoclax-treated patients with chronic lymphocytic leukaemia. Br. J. Haematol. 188, 844–851 (2020).

    PubMed  Google Scholar 

  103. Seymour, J. F. et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 18, 230–240 (2017). This study demonstrates in patients with relapsed and/or refractory CLL that the combination of venetoclax plus rituximab can result in significantly higher rates of PFS compared with bendamustine plus rituximab.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02005471 (2013).

  105. Kater, A. P. et al. Venetoclax plus rituximab in relapsed chronic lymphocytic Leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J. Clin. Oncol. 38, 4042–4054 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Kater, A. P. et al. Five-year analysis of Murano Study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (pts) following fixed-duration venetoclax-rituximab (VenR) therapy (Tx). Blood 136 (Suppl. 1), 19–21 (2020).

    Google Scholar 

  107. Rogers, K. A. et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood 132, 1568–1572 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Fischer, K. et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N. Engl. J. Med. 380, 2225–2236 (2019).

    CAS  PubMed  Google Scholar 

  109. Zenz, T. et al. TP53 mutation and survival in chronic lymphocytic leukemia. J. Clin. Oncol. 28, 4473–4479 (2010).

    PubMed  Google Scholar 

  110. Rossi, D. et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 123, 2139–2147 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02910583 (2016).

  112. Wierda, W. G. et al. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Blood 136 (Suppl. 1), 16–17 (2020).

    Google Scholar 

  113. Davids, M. S. et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J. Clin. Oncol. 35, 826–833 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Tam, C. S. et al. Ibrutinib plus Venetoclax for the treatment of mantle-cell lymphoma. N. Engl. J. Med. 378, 1211–1223 (2018).

    CAS  PubMed  Google Scholar 

  115. Castillo, J. J. et al. Multicenter prospective phase II study of venetoclax in patients with previously treated Waldenstrom macroglobulinemia. Blood 132 (Suppl. 1), 2888 (2018).

    Google Scholar 

  116. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02187861 (2014).

  117. Zinzani, P. L. et al. Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma. Blood 136, 2628–2637 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bodo, J. et al. Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells. Oncotarget 7, 70000–70010 (2016).

    PubMed  PubMed Central  Google Scholar 

  119. Morschhauser, F. et al. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood 137, 600–609 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02055820 (2014).

  121. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03984448 (2019).

  122. Kumar, S. et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 130, 2401–2409 (2017). This study describes the clinical evaluation of venetoclax in combination with standard-of-care drugs for relapsed and/or refractory MM.

    CAS  PubMed  Google Scholar 

  123. Kumar, S. K. et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 21, 1630–1642 (2020).

    CAS  PubMed  Google Scholar 

  124. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02755597 (2016).

  125. Konopleva, M. et al. 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 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. DiNardo, C. D. et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133, 7–17 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. DiNardo, C. D. et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N. Engl. J. Med. 383, 617–629 (2020). This study describes the clinical evaluation of venetoclax in combination with the HMA azacytidine for therapy for AML, providing evidence of longer overall survival and higher incidence of remission compared with azacytidine plus placebo.

    CAS  PubMed  Google Scholar 

  128. DiNardo, C. D. et al. Venetoclax combined with FLAG-IDA Induction and consolidation in newly diagnosed and relapsed or refractory acute myeloid leukemia. J. Clin. Oncol. https://doi.org/10.1200/JCO.20.03736 (2021).

    Article  PubMed  Google Scholar 

  129. Khaw, S. L. et al. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood 128, 1382–1395 (2016).

    PubMed  PubMed Central  Google Scholar 

  130. Pullarkat, V. A. et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer Discov. 11, 1440–1453 (2021).

    CAS  PubMed  Google Scholar 

  131. Jain, N. et al. A multicenter phase I study combining venetoclax with mini-hyper-CVD in older adults with untreated and relapsed/refractory acute lymphoblastic leukemia. Blood 134 (Suppl. 1), 3867 (2019).

    Google Scholar 

  132. Lok, S. W. et al. A Phase Ib dose-escalation and expansion study of the BCL2 inhibitor venetoclax combined with tamoxifen in ER and BCL2-positive metastatic breast cancer. Cancer Discov. 9, 354–369 (2019).

    CAS  PubMed  Google Scholar 

  133. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03900884 (2019).

  134. Muttiah, C. et al. Abstract OT-27-01: PALVEN: a phase 1b study of palbociclib, letrozole and venetoclax in estrogen receptor, BCL2-positive metastatic breast cancer. Cancer Res. https://doi.org/10.1158/1538-7445.SABCS20-OT-27-01 (2021).

    Article  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03584009 (2018).

  136. Lindeman, G. et al. Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC). J. Clin. Oncol. 39 (15 Suppl.), 1004 (2021).

    Google Scholar 

  137. Arbour, N. et al. Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage. J. Neurosci. 28, 6068–6078 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02471391 (2015).

  139. Agarwal, R. et al. Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat. Med. 25, 119–129 (2019).

    CAS  PubMed  Google Scholar 

  140. Chueh, A. C. et al. ATF3 repression of BCL-XL determines apoptotic sensitivity to HDAC inhibitors across tumor types. Clin. Cancer Res. 23, 5573–5584 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Fresquet, V., Rieger, M., Carolis, C., Garcia-Barchino, M. J. & Martinez-Climent, J. A. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood 123, 4111–4119 (2014).

    CAS  PubMed  Google Scholar 

  142. Blombery, P. et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 9, 342–353 (2019). This study identifies mutations in BCL-2 itself conferring resistance to venetoclax in patients with CLL receiving therapy.

    CAS  PubMed  Google Scholar 

  143. Tausch, E. et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 104, e434–e437 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Villunger, A. et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science 302, 1036–1038 (2003).

    CAS  PubMed  Google Scholar 

  145. Birkinshaw, R. W. et al. Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat. Commun. 10, 2385 (2019).

    PubMed  PubMed Central  Google Scholar 

  146. Blombery, P. et al. Characterization of a novel venetoclax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma. Br. J. Haematol. 186, e188–e191 (2019).

    PubMed  Google Scholar 

  147. Guieze, R. et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell 36, 369–384 e313 (2019). This study identifies factors that can confer resistance to BH3-mimetic drugs targeting BCL-2.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Tahir, S. K. et al. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer 17, 399 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. Lin, K. H. et al. Targeting MCL-1/BCL-XL forestalls the acquisition of resistance to ABT-199 in acute myeloid leukemia. Sci. Rep. 6, 27696 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhao, X. et al. BCL2 amplicon loss and transcriptional remodeling drives ABT-199 resistance in B cell lymphoma models. Cancer Cell 35, 752–766 e759 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Nechiporuk, T. et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 9, 910–925 (2019). This study identifies defects in p53 that can confer resistance to BH3-mimetic drugs targeting BCL-2 in AML cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Chen, X. et al. Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment. Cancer Discov. 9, 890–909 (2019). This study identifies mitochondrial factors that are important for responses to venetoclax in AML cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Thijssen, R. et al. Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias. Blood 137, 2721–2735 (2021). This study demonstrates that loss of p53 function can confer resistance to both BCL-2-targeting and MCL-1-targeting BH3-mimetic drugs and interrogates the underlying mechanisms of this resistance.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Moujalled, D. M. et al. Acquired mutations in BAX confer resistance to BH3 mimetics in acute myeloid leukemia. Blood 136 (Suppl. 1), 7–8 (2020).

    Google Scholar 

  155. Blombery, P. et al. BAX-mutated clonal hematopoiesis in patients on long-term venetoclax for relapsed/refractory chronic lymphocytic leukemia. Blood 136 (Suppl. 1), 9–10 (2020).

    Google Scholar 

  156. Roberts, A. W. et al. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood 134, 111–122 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Chua, C. C. et al. Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): a phase Ib dose-escalation study of venetoclax combined with modified intensive chemotherapy. J. Clin. Oncol. 38, 3506–3517 (2020).

    CAS  PubMed  Google Scholar 

  158. Wei, A. H. et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood 135, 2137–2145 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Savona, M. R. & Rathmell, J. C. Mitochondrial homeostasis in AML and gasping for response in resistance to BCL2 blockade. Cancer Discov. 9, 831–833 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Herling, C. D. et al. Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat. Commun. 9, 727 (2018).

    PubMed  PubMed Central  Google Scholar 

  161. Ramsey, H. E. et al. A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia. Cancer Discov. 8, 1566–1581 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Teh, T. C. et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia 32, 303–312 (2018).

    CAS  PubMed  Google Scholar 

  163. Jayappa, K. D. et al. Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL. Blood Adv. 1, 933–946 (2017). This article describes how cells within the tumour microenvironment can provide survival signals that lead to increased expression of certain prosurvival proteins within CLL and mantle cell lymphoma cells residing in the niche, thereby conferring upon the malignant cells resistance to venetoclax combined with ibrutinib while they are within this niche.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Chiron, D. et al. Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma. Blood 128, 2808–2818 (2016).

    CAS  PubMed  Google Scholar 

  165. Lin, V. S. et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood 135, 2266–2270 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Hillmen, P. et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J. Clin. Oncol. 37, 2722–2729 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Munir, T. et al. Continued long term responses to ibrutinib + venetoclax treatment for relapsed/refractory CLL in the Blood Cancer UK TAP Clarity trial. Blood 136 (Suppl. 1), 17–18 (2020).

    Google Scholar 

  168. ISRCTN Registry. Assessment of venetoclax in combination with Ibrutinib in patients with Chronic Lymphocytic Leukaemia Isrctn.com https://www.isrctn.com/ISRCTN13751862 (2016).

  169. Certo, M. et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9, 351–365 (2006).

    CAS  PubMed  Google Scholar 

  170. Chonghaile, T. N. et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129–1133 (2011).

    CAS  PubMed Central  Google Scholar 

  171. Ishikawa, K. et al. BH3 profiling discriminates the antiapoptotic status of 5fluorouracilresistant colon cancer cells. Oncol. Rep. 42, 2416–2425 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Deng, J. et al. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 12, 171–185 (2007).

    CAS  PubMed  Google Scholar 

  173. Bhatt, S. et al. Reduced mitochondrial apoptotic priming drives resistance to BH3 mimetics in acute myeloid leukemia. Cancer Cell 38, 872–890 e876 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Montero, J. et al. Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies. Nat. Commun. 10, 5157 (2019).

    PubMed  PubMed Central  Google Scholar 

  175. Sale, M. J. et al. Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors. Nat. Commun. 10, 5167 (2019).

    PubMed  PubMed Central  Google Scholar 

  176. Lin, K. H. et al. Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer. Nat. Genet. 52, 408–417 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Koch, R. et al. Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas. Blood 133, 566–575 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03595059 (2018).

  179. Patterson, C. M. et al. Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy. Commun. Biol. 4, 112 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Maeda, H. Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv. Drug Deliv. Rev. 91, 3–6 (2015).

    CAS  PubMed  Google Scholar 

  181. Bai, L. et al. BM-1252 (APG-1252): a potent dual specific Bcl-2/Bcl-xL inhibitor that achieves complete tumor regression with minimal platelet toxicity. Eur. J. Cancer 50, 109–110 (2014).

    Google Scholar 

  182. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04214093 (2019).

  183. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03080311 (2017).

  184. Lakhani, N. J. et al. First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors. J. Clin. Oncol. 38 (15 Suppl.), 3509 (2020).

    Google Scholar 

  185. Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. 18, 949–963 (2019).

    CAS  PubMed  Google Scholar 

  186. He, Y. et al. DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J. Hematol. Oncol. 13, 95 (2020).

    PubMed  PubMed Central  Google Scholar 

  187. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04886622 (2021).

  188. Papatzimas, J. W. et al. From inhibition to degradation: targeting the antiapoptotic protein myeloid cell leukemia 1 (MCL1). J. Med. Chem. 62, 5522–5540 (2019).

    CAS  PubMed  Google Scholar 

  189. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03672695 (2018).

  190. Bala Tannan, N. et al. Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition. Blood 137, 2057–2069 (2021). This article describes a novel approach to deliver BH3-mimetic drugs targeting MCL-1 and BCL-2 to tumour cells by encapsulating them in nanoparticles that target P-selectin, which is enriched in tumour endothelial cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01328626 (2011).

  192. Stilgenbauer, S. et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J. Clin. Oncol. 36, 1973–1980 (2018).

    CAS  PubMed  Google Scholar 

  193. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01889186 (2013).

  194. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01682616 (2012).

  195. Kater, A. P. et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-pp of the MURANO phase III study. J. Clin. Oncol. 37, 269–277 (2019).

    CAS  PubMed  Google Scholar 

  196. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02427451 (2015).

  197. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02242942 (2014).

  198. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01794520 (2013).

  199. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02677324 (2016).

  200. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01994837 (2013).

  201. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03214562 (2017).

  202. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02203773 (2014).

  203. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02993523 (2016).

  204. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03181126 (2017).

  205. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02675452 (2016).

  206. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02979366 (2016).

  207. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02992483 (2016).

  208. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03218683 (2017).

  209. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03797261 (2019).

  210. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03465540 (2018).

  211. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04178902 (2019).

  212. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04543305 (2020).

  213. Czabotar, P. E. et al. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc. Natl Acad. Sci. USA 104, 6217–6222 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Lee, E. F. et al. Crystal structure of ABT-737 complexed with Bcl-x(L): implications for selectivity of antagonists of the Bcl-2 family. Cell Death Differ. 14, 1711–1713 (2007).

    CAS  PubMed  Google Scholar 

  215. Lessene, G. et al. Structure-guided design of a selective BCL-xL inhibitor. Nat. Chem. Biol. 9, 390–397 (2013). This article describes a BCL-XL-specific BH3-mimetic compound.

    CAS  PubMed  Google Scholar 

  216. Wang, L. et al. Discovery of A-1331852, a first-in-class, potent, and orally-bioavailable BCL-XL inhibitor. ACS Med. Chem. Lett. 11, 1829–1836 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Rescourio, G. et al. Discovery and in vivo evaluation of macrocyclic Mcl-1 inhibitors featuring an alpha-hydroxy phenylacetic acid pharmacophore or bioisostere. J. Med. Chem. 62, 10258–10271 (2019).

    CAS  PubMed  Google Scholar 

  218. Strasser, A., Harris, A. W., Bath, M. L. & Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331–333 (1990).

    CAS  PubMed  Google Scholar 

  219. Vaux, D. L., Aguila, H. L. & Weissman, I. L. Bcl-2 prevents death of factor-deprived cells but fails to prevent apoptosis in targets of cell mediated killing. Int. Immunol. 4, 821–824 (1992).

    CAS  PubMed  Google Scholar 

  220. Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988).

    CAS  PubMed  Google Scholar 

  221. Campbell, K. J. et al. Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance. Blood 116, 3197–3207 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Swanson, P. J. et al. Fatal acute lymphoblastic leukemia in mice transgenic for B cell-restricted bcl-xL and c-myc. J. Immunol. 172, 6684–6691 (2004).

    CAS  PubMed  Google Scholar 

  223. Egle, A., Harris, A. W., Bouillet, P. & Cory, S. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc. Natl Acad. Sci. USA 101, 6164–6169 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Garrison, S. P. et al. Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol. Cell Biol. 28, 5391–5402 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Michalak, E. M. et al. Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death Differ. 16, 684–696 (2009).

    CAS  PubMed  Google Scholar 

  226. Tsujimoto, Y., Finger, L. R., Yunis, J., Nowell, P. C. & Croce, C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226, 1097–1099 (1984).

    CAS  PubMed  Google Scholar 

  227. Cleary, M. L. & Sklar, J. Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc. Natl Acad. Sci. USA 82, 7439–7443 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Bakhshi, A. et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41, 899–906 (1985).

    CAS  PubMed  Google Scholar 

  229. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Calin, G. A. et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 99, 15524–15529 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Calin, G. A. et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N. Engl. J. Med. 353, 1793–1801 (2005).

    CAS  PubMed  Google Scholar 

  232. Cimmino, A. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102, 13944–13949 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Richter-Larrea, J. A. et al. Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma. Blood 116, 2531–2542 (2010).

    CAS  PubMed  Google Scholar 

  234. Mestre-Escorihuela, C. et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 109, 271–280 (2007).

    CAS  PubMed  Google Scholar 

  235. Tagawa, H. et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 24, 1348–1358 (2005).

    CAS  PubMed  Google Scholar 

  236. Cragg, M. S., Harris, C., Strasser, A. & Scott, C. L. Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat. Rev. Cancer 9, 321–326 (2009).

    CAS  PubMed  Google Scholar 

  237. Petros, A. M. et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci. 9, 2528–2534 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Sattler, M. et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983–986 (1997).

    CAS  PubMed  Google Scholar 

  239. Petros, A. M. et al. Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J. Med. Chem. 49, 656–663 (2006).

    CAS  PubMed  Google Scholar 

  240. Park, C. M. et al. Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J. Med. Chem. 51, 6902–6915 (2008).

    CAS  PubMed  Google Scholar 

  241. Wendt, M. D. et al. Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo. J. Med. Chem. 49, 1165–1181 (2006).

    CAS  PubMed  Google Scholar 

  242. van Delft, M. F. et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389–399 (2006).

    PubMed  PubMed Central  Google Scholar 

  243. Sleebs, B. E. et al. Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL. J. Med. Chem. 56, 5514–5540 (2013).

    CAS  PubMed  Google Scholar 

  244. Koehler, M. F. et al. Structure-guided rescaffolding of selective antagonists of BCL-XL. ACS Med. Chem. Lett. 5, 662–667 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Tao, Z. F. et al. Discovery of a potent and selective BCL-XL inhibitor with in vivo activity. ACS Med. Chem. Lett. 5, 1088–1093 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Leverson, J. D. et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci. Transl. Med. 7, 279ra240 (2015).

    Google Scholar 

  247. Wei, A. H. et al. Targeting MCL-1 in hematologic malignancies: rationale and progress. Blood Rev. 44, 100672 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Murray, J. B. et al. Establishing drug discovery and identification of hit series for the anti-apoptotic proteins, Bcl-2 and Mcl-1. ACS Omega 4, 8892–8906 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Szlavik, Z. et al. Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity. J. Med. Chem. 62, 6913–6924 (2019).

    CAS  PubMed  Google Scholar 

  250. Bruncko, M. et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J. Med. Chem. 58, 2180–2194 (2015).

    CAS  PubMed  Google Scholar 

  251. Lee, T. et al. Discovery of potent myeloid cell leukemia-1 (Mcl-1) inhibitors that demonstrate in vivo activity in mouse xenograft models of human cancer. J. Med. Chem. 62, 3971–3988 (2019).

    CAS  PubMed  Google Scholar 

  252. Veis, D. J., Sorenson, C. M., Shutter, J. R. & Korsmeyer, S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75, 229–240 (1993).

    CAS  PubMed  Google Scholar 

  253. Kamada, S. et al. bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Res. 55, 354–359 (1995).

    CAS  PubMed  Google Scholar 

  254. Nakayama, K.-I. et al. Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 261, 1584–1588 (1993).

    CAS  PubMed  Google Scholar 

  255. Nakayama, K. et al. Targeted disruption of bcl-2ab in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc. Natl Acad. Sci. USA 91, 3700–3704 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Motoyama, N. et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267, 1506–1510 (1995).

    CAS  PubMed  Google Scholar 

  257. Ma, A. et al. Bclx regulates the survival of double-positive thymocytes. Proc. Natl Acad. Sci. USA 92, 4763–4767 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Wagner, K. U. et al. Conditional deletion of the Bcl-x gene from erythroid cells results in hemolytic anemia and profound splenomegaly. Development 127, 4949–4958 (2000).

    CAS  PubMed  Google Scholar 

  259. Brinkmann, K. et al. BCL-XL exerts a protective role against anemia caused by radiation-induced kidney damage. EMBO J. https://doi.org/10.15252/embj.2020105561 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Rinkenberger, J. L., Horning, S., Klocke, B., Roth, K. & Korsmeyer, S. J. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes \Dev. 14, 23–27 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Grabow, S. et al. Subtle changes in the levels of BCL-2 proteins cause severe craniofacial abnormalities. Cell Rep. 24, 3285–3295 e3284 (2018).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The work by the authors was supported by fellowships and grants from the Australian National Health and Medical Research Council (NHMRC) (Program Grant GNT1113133 to A.S. and G.L., Research Fellowships GNT1117089 to G.L., GNT1079700 to P.E.C. and GNT1116937 to A.S., Project Grants GNT1143105 to A.S. and GNT1158137 to P.E.C., Investigator Grant GNT1177718 to M.A.A. and Ideas Grants GNT 2002618 and GNT2001201 to G.L.K. and GNT2001406 to P.E.C.), the Leukemia & Lymphoma Society of America (Specialized Center of Research Program grant no. 7015-18 to A.S., G.L.K. and G.L.), the Victorian Cancer Agency (MCRF fellowship 17028 to G.L.K.), the estate of Anthony (Toni) Redstone OAM(A.S. and G.L.K.), the Craig Perkins Cancer Research Foundation (G.L.K.), the Jack Brockhoff Foundation (M.A.A.) and the Dyson Bequest (G.L.K.). Work in the laboratories of the authors was made possible through the Victorian State Government Operational Infrastructure Support Program and the Australian Government NHMRC Independent Research Institute Infrastructure Support Scheme. The authors acknowledge A. Wei for discussions, C. McLean for assistance with the preparation of this Review and E. Conti for drafting of figures.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

    Sarah T. Diepstraten, Mary Ann Anderson, Peter E. Czabotar, Guillaume Lessene, Andreas Strasser & Gemma L. Kelly

  2. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia

    Sarah T. Diepstraten, Mary Ann Anderson, Peter E. Czabotar, Guillaume Lessene, Andreas Strasser & Gemma L. Kelly

  3. Department of Clinical Haematology, Royal Melbourne Hospital, Melbourne, VIC, Australia

    Mary Ann Anderson

  4. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Mary Ann Anderson

  5. Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia

    Guillaume Lessene

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Contributions

All authors researched data for the article. G.L.K. S.T.D. and A.S. contributed substantially to discussion of the content. All authors contributed to the writing of the article. S.T.D., A.S. and G.L.K. reviewed and/or edited the manuscript before submission.

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Correspondence to Andreas Strasser or Gemma L. Kelly.

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All authors are employees of the Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax. G.L., A.S. and G.L.K. have received research funding from Servier. M.A.A. receives honoraria from AbbVie, Janssen, Novartis and Beigene.

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Glossary

Apoptosome

A multiprotein complex composed of the adaptor protein APAF1, cytochrome c (released from the intermitochondrial space after activation of BAX and BAK) and procaspase 9 that promotes activation of caspase 9; this complex activates the effector caspases, unleashing dismantling of the cells undergoing apoptosis.

K i

Dissociation constant for the interaction of, for example, a drug binding to its protein target.

Hypomethylating agents

(HMAs). Drugs used for cancer treatment that inhibit DNA methylation and thereby perturb epigenetic regulation in cells.

Thrombocytopenia

A reduction in platelet count.

Tumour lysis syndrome

(TLS). A condition that can be life-threatening that occurs when large numbers of tumour cells die within a short period, releasing their contents into the blood, which can cause stress to the kidneys.

Uric acid-lowering agents

Drugs that reduce the levels of uric acid in the blood; this can prevent kidney damage during tumour lysis syndrome.

Undetectable minimal residual disease

(uMRD). The absence of chronic lymphocytic leukaemia cells in a patient after therapy.

Hypogammaglobulinaemia

Abnormally low levels of antibodies (immunoglobulins).

Composite complete response

(CRc). State in which the original blood cell cancer no longer persists and the blood cell counts in a patient have been normalized.

Lymphopenia

Abnormal reduction in lymphocyte count.

Clinical benefit rate

The percentage of patients with advanced or metastatic cancer who have achieved complete remission, partial remission and stable disease owing to a therapeutic intervention in clinical trials of anticancer agents.

Richter transformation

An uncommon clinicopathological condition observed in about 5–10% of patients with chronic lymphocytic leukaemia that refers to the development of aggressive lymphoma during the course of chronic lymphocytic leukaemia.

Amplicon

A section of chromosomal DNA that has been amplified.

Surface plasmon resonance

The resonant oscillation of conduction electrons at the interface between negative-permittivity and positive-permittivity material stimulated by incident light. It is the basis of many standard tools for measuring adsorption of material onto planar metal (typically gold or silver) surfaces and is the fundamental principle behind many colour-based biosensor applications.

Antibody–drug conjugates

Highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific for surface antigens present on particular tumour cells with highly potent anticancer agents linked via a chemical linker.

Dendrimer

A highly ordered, branched polymeric molecule.

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Diepstraten, S.T., Anderson, M.A., Czabotar, P.E. et al. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nat Rev Cancer 22, 45–64 (2022). https://doi.org/10.1038/s41568-021-00407-4

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