[en] Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
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. 2019;20:175–93. DOI: 10.1038/s41580-018-0089-8
Sarosiek KA, et al. Developmental regulation of mitochondrial apoptosis by c-myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell. 2017;31:142–56. DOI: 10.1016/j.ccell.2016.11.011
Gutierrez-Martinez P, et al. Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat Cell Biol. 2018;20:413–21. DOI: 10.1038/s41556-018-0054-y
Sarosiek KA, Letai A. Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics - recent successes, current challenges and future promise. FEBS J. 2016;283:3523–33. DOI: 10.1111/febs.13714
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. 2007;12:171–85. DOI: 10.1016/j.ccr.2007.07.001
Touzeau C, et al. BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics. Leukemia. 2016;30:761–4. DOI: 10.1038/leu.2015.184
Gong J-N, et al. Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood. 2016;128:1834–44. DOI: 10.1182/blood-2016-03-704908
Tsherniak A, et al. Defining a cancer dependency map. Cell. 2017;170:564-576.e16. DOI: 10.1016/j.cell.2017.06.010
Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci U S A. 1993;90:3516–20. DOI: 10.1073/pnas.90.8.3516
Petros AM, Olejniczak ET, Fesik SW. Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta Mol Cell Res. 2004;1644:83–94. DOI: 10.1016/j.bbamcr.2003.08.012
Sattler M, et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science. 1997;275:983–6. DOI: 10.1126/science.275.5302.983
Denis C, Sopková-de Oliveira Santos J, Bureau R, Voisin-Chiret AS. Hot-Spots of Mcl-1 Protein. J Med Chem. 2020;63:928–43. DOI: 10.1021/acs.jmedchem.9b00983
Senichkin VV, Streletskaia AY, Gorbunova AS, Zhivotovsky B, Kopeina GS. Saga of Mcl-1: regulation from transcription to degradation. Cell Death Differ. 2020;27:405–19. DOI: 10.1038/s41418-019-0486-3
Cl, D. et al. Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands. J Biol Chem 2005.
Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 2018;25:65–80. DOI: 10.1038/cdd.2017.186
Day CL, et al. Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. J Mol Biol. 2008;380:958–71. DOI: 10.1016/j.jmb.2008.05.071
Opferman JT, et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature. 2003;426:671–6. DOI: 10.1038/nature02067
Senichkin VV, Streletskaia AY, Zhivotovsky B, Kopeina GS. Molecular comprehension of Mcl-1: from gene structure to cancer therapy. Trends Cell Biol. 2019;29:549–62. DOI: 10.1016/j.tcb.2019.03.004
Wang X, et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev. 2013;27:1351–64. DOI: 10.1101/gad.215855.113
Perciavalle RM, et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol. 2012;14:575–83. DOI: 10.1038/ncb2488
Rasmussen ML, et al. A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells. Stem Cell Reports. 2018;10:684–92. DOI: 10.1016/j.stemcr.2018.01.005
Rasmussen, M. L. et al. MCL-1 Inhibition by selective BH3 mimetics disrupts mitochondrial dynamics causing loss of viability and functionality of human cardiomyocytes. iScience 23, (2020).
Chen G, et al. Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy. J Clin Invest. 2018;128:500–16. DOI: 10.1172/JCI92742
Germain M, et al. MCL-1 is a stress sensor that regulates autophagy in a developmentally regulated manner. EMBO J. 2011;30:395–407. DOI: 10.1038/emboj.2010.327
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. DOI: 10.1016/j.cell.2011.02.013
AACR Project GENIE. Powering precision medicine through an international consortium. Cancer Discov. 2017;7:818–31. DOI: 10.1158/2159-8290.CD-17-0151
Lv X, et al. Somatic mutations in myeloid cell leukemia-1 contribute to the pathogenesis of glioma by prolonging its half-life. Mol Med Rep. 2015;12:1265–71. DOI: 10.3892/mmr.2015.3493
Beroukhim R, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905. DOI: 10.1038/nature08822
Campbell KJ, et al. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis. 2018;9:1–14. DOI: 10.1038/s41419-017-0035-2
Zhou P, et al. MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood. 2001;97:3902–9. DOI: 10.1182/blood.V97.12.3902
Grabow S, Delbridge ARD, Aubrey BJ, Vandenberg CJ, Strasser A. Loss of a single Mcl-1 allele inhibits MYC-driven lymphomagenesis by sensitizing pro-B cells to apoptosis. Cell Rep. 2016;14:2337–47. DOI: 10.1016/j.celrep.2016.02.039
Glaser SP, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26:120–5. DOI: 10.1101/gad.182980.111
Grabow S, Delbridge ARD, Valente LJ, Strasser A. MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice. Blood. 2014;124:3939–46. DOI: 10.1182/blood-2014-09-601567
Spinner S, et al. Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance. Leukemia. 2016;30:1520–30. DOI: 10.1038/leu.2016.49
Schwickart M, et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463:103–7. DOI: 10.1038/nature08646
Wei G, et al. Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. Cancer Cell. 2012;21:547–62. DOI: 10.1016/j.ccr.2012.02.028
Brunelle JK, Ryan J, Yecies D, Opferman JT, Letai A. MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts. J Cell Biol. 2009;187:429–42. DOI: 10.1083/jcb.200904049
Wertz IE, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471:110–4. DOI: 10.1038/nature09779
Yeh C-H, Bellon M, Pancewicz-Wojtkiewicz J, Nicot C. Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients. Proc Natl Acad Sci U S A. 2016;113:6731–6. DOI: 10.1073/pnas.1601537113
Inuzuka H, et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011;471:104–9. DOI: 10.1038/nature09732
Min S-H, et al. Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol Cell. 2012;46:771–83. DOI: 10.1016/j.molcel.2012.04.012
Peterson LF, et al. Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies. Blood. 2015;125:3588–97. DOI: 10.1182/blood-2014-10-605584
Zhang S, et al. Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors. Nat Commun. 2018;9:215. DOI: 10.1038/s41467-017-02693-9
Lee K-M, et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab. 2017;26:633-647.e7. DOI: 10.1016/j.cmet.2017.09.009
Wei G, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell. 2006;10:331–42. DOI: 10.1016/j.ccr.2006.09.006
Elgendy M, et al. Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3β-MCL-1 axis. Cancer Cell. 2019;35:798-815.e5. DOI: 10.1016/j.ccell.2019.03.007
Ni Chonghaile T, et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011;334:1129–33. DOI: 10.1126/science.1206727
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. 2018;8:1598–613. DOI: 10.1158/2159-8290.CD-18-0277
Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Song K-A, et al. Increased Synthesis of MCL-1 protein underlies initial survival of EGFR-mutant lung cancer to EGFR inhibitors and provides a novel drug target. Clin cancer Res. 2018;24:5658–72. DOI: 10.1158/1078-0432.CCR-18-0304
Borner MM, et al. Expression of apoptosis regulatory proteins of the Bcl-2 family and p53 in primary resected non-small-cell lung cancer. Br J Cancer. 1999;79:952–8. DOI: 10.1038/sj.bjc.6690152
Nakano T, Go T, Nakashima N, Liu D, Yokomise H. Overexpression of antiapoptotic MCL-1 predicts worse overall survival of patients with non-small cell lung cancer. Anticancer Res. 2020;40:1007–14. DOI: 10.21873/anticanres.14035
Inoue-Yamauchi A, et al. Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy. Nat Commun. 2017;8:16078. DOI: 10.1038/ncomms16078
Yasuda Y, et al. MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-X(L) expression. Cell Death Dis. 2020;11:177. DOI: 10.1038/s41419-020-2379-2
Perillo B, Sasso A, Abbondanza C, Palumbo G. 17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol Cell Biol. 2000;20:2890–901. DOI: 10.1128/MCB.20.8.2890-2901.2000
Louault K, et al. Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers. Oncogene. 2019;38:3261–73. DOI: 10.1038/s41388-018-0635-z
Ding Q, et al. Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. Cancer Res. 2007;67:4564–71. DOI: 10.1158/0008-5472.CAN-06-1788
Williams MM, et al. Key survival factor, Mcl-1, correlates with sensitivity to combined Bcl-2/Bcl-xL blockade. Mol Cancer Res. 2017;15:259–68. DOI: 10.1158/1541-7786.MCR-16-0280-T
Balko JM, et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2014;4:232–45. DOI: 10.1158/2159-8290.CD-13-0286
Williams MM, et al. Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers. Oncotarget. 2019;10:5389–402. DOI: 10.18632/oncotarget.27070
Vallet S, et al. Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer. Breast Cancer Res Treat. 2019;173:585–96. DOI: 10.1007/s10549-018-5022-5
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. 9, (2017).
Lim SY, Menzies AM, Rizos H. Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma. Cancer. 2017;123:2118–29. DOI: 10.1002/cncr.30435
Cook SJ, Stuart K, Gilley R, Sale MJ. Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling. FEBS J. 2017;284:4177–95. DOI: 10.1111/febs.14122
Lee EF, et al. BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival. Cell Death Dis. 2019a;10:342. DOI: 10.1038/s41419-019-1568-3
Mukherjee N, et al. Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells. Oncotarget. 2017;8:46801–17. DOI: 10.18632/oncotarget.8695
Sale MJ, et al. Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors. Nat Commun. 2019;10:5167. DOI: 10.1038/s41467-019-12409-w
Lee W-S, et al. Myeloid cell leukemia-1 is associated with tumor progression by inhibiting apoptosis and enhancing angiogenesis in colorectal cancer. Am J Cancer Res. 2015;5:101–13.
Wilhelm SM, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40. DOI: 10.1158/1535-7163.MCT-08-0013
Yu C, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43–9006. Oncogene. 2005;24:6861–9. DOI: 10.1038/sj.onc.1208841
Tong J, Tan S, Zou F, Yu J, Zhang L. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene. 2017;36:787–96. DOI: 10.1038/onc.2016.247
Tong J, et al. Mcl-1 degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Res. 2017;77:2512–21. DOI: 10.1158/0008-5472.CAN-16-3242
He K, et al. BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells. Oncotarget. 2016;7:47699–710. DOI: 10.18632/oncotarget.10277
Kawakami H, et al. Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer. Mol Cancer Ther. 2016;15:3015–27. DOI: 10.1158/1535-7163.MCT-16-0017
Lin L, et al. Trametinib potentiates TRAIL-induced apoptosis via FBW7-dependent Mcl-1 degradation in colorectal cancer cells. J Cell Mol Med. 2020;24:6822–32. DOI: 10.1111/jcmm.15336
Song X, et al. Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer. Theranostics. 2020;10:8098–110. DOI: 10.7150/thno.45363
Slomp A, Peperzak V. Role and regulation of pro-survival BCL-2 proteins in multiple myeloma. Front Oncol. 2018;8:533. DOI: 10.3389/fonc.2018.00533
Chonghaile TN, et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov. 2014;4:1074–87. DOI: 10.1158/2159-8290.CD-14-0353
Pei S, et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov. 2020;10:536–51. DOI: 10.1158/2159-8290.CD-19-0710
Peperzak V, et al. Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 2013;14:290–7. DOI: 10.1038/ni.2527
Derenne S, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood. 2002;100:194–9. DOI: 10.1182/blood.V100.1.194
Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood. 2002;99:1885–93. DOI: 10.1182/blood.V99.6.1885
Kumar S, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130:2401–9. DOI: 10.1182/blood-2017-06-788786
Bajpai R, et al. Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma. Nat Commun. 2020;11:1228. DOI: 10.1038/s41467-020-15051-z
Touzeau C, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210–2. DOI: 10.1038/leu.2013.216
Wuillème-Toumi S, et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia. 2005;19:1248–52. DOI: 10.1038/sj.leu.2403784
Gomez-Bougie P, et al. BH3-mimetic toolkit guides the respective use of BCL2 and MCL1 BH3-mimetics in myeloma treatment. Blood. 2018;132:2656–69. DOI: 10.1182/blood-2018-03-836718
Morales AA, et al. Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells. Blood. 2011;118:1329–39. DOI: 10.1182/blood-2011-01-327197
Seiller C, et al. Dual targeting of BCL2 and MCL1 rescues myeloma cells resistant to BCL2 and MCL1 inhibitors associated with the formation of BAX/BAK hetero-complexes. Cell Death Dis. 2020;11:316. DOI: 10.1038/s41419-020-2505-1
Slomp A, et al. Multiple myeloma with 1q21 amplification is highly sensitive to MCL-1 targeting. Blood Adv. 2019;3:4202–14. DOI: 10.1182/bloodadvances.2019000702
Jourdan M, De Vos J, Mechti N, Klein B. Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. Cell Death Differ. 2000;7:1244–52. DOI: 10.1038/sj.cdd.4400758
Gupta VA, et al. Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma. Blood. 2017;129:1969–79. DOI: 10.1182/blood-2016-10-745059
De Veirman, K. et al. Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells. Oncotarget 6, (2015).
Gomez-Bougie P, Oliver L, Le Gouill S, Bataille R, Amiot M. Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex. Oncogene. 2005;24:8076–9. DOI: 10.1038/sj.onc.1208949
Podar K, et al. A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. Oncogene. 2008;27:721–31. DOI: 10.1038/sj.onc.1210679
Gomez-Bougie P, et al. Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. Cancer Res. 2007;67:5418–24. DOI: 10.1158/0008-5472.CAN-06-4322
Fan F, et al. Targeting Mcl-1 for multiple myeloma (MM) therapy: drug-induced generation of Mcl-1 fragment Mcl-1(128–350) triggers MM cell death via c-Jun upregulation. Cancer Lett. 2014;343:286–94. DOI: 10.1016/j.canlet.2013.09.042
Tunquist BJ, Woessner RD, Walker DH. Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther. 2010;9:2046–56. DOI: 10.1158/1535-7163.MCT-10-0033
Davids MS, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35:826–33. DOI: 10.1200/JCO.2016.70.4320
Hughes ME, et al. Treatment of patients with relapsed/refractory non-hodgkin lymphoma with venetoclax: a single-center evaluation of off-label use. Clin Lymphoma Myeloma Leuk. 2019;19:791–8. DOI: 10.1016/j.clml.2019.09.612
Prukova D, et al. Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. Clin Cancer Res. 2019;25:4455–65. DOI: 10.1158/1078-0432.CCR-18-3275
Phillips DC, et al. Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2015;5:e368. DOI: 10.1038/bcj.2015.88
Smith VM, et al. Dual dependence on BCL2 and MCL1 in T-cell prolymphocytic leukemia. Blood Adv. 2020a;4:525–9. DOI: 10.1182/bloodadvances.2019000917
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. 2018;8:1582–97.
Smith VM, et al. Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma. Haematologica. 2020b;105:2150–63. DOI: 10.3324/haematol.2019.220525
Kotschy A, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538:477–82. DOI: 10.1038/nature19830
Manzano M, et al. Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma. Nat Commun. 2018;9:3263. DOI: 10.1038/s41467-018-05506-9
Zhao S, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. Am J Hematol. 2020;95:623–9. DOI: 10.1002/ajh.25796
Kelly GL, et al. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev. 2014;28:58–70. DOI: 10.1101/gad.232009.113
Kitada S, et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood. 1998;91:3379–89. DOI: 10.1182/blood.V91.9.3379
Bannerji R, et al. Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21:1466–71. DOI: 10.1200/JCO.2003.06.012
Balakrishnan K, et al. Regulation of Mcl-1 expression in context to bone marrow stromal microenvironment in chronic lymphocytic leukemia. Neoplasia. 2014;16:1036–46. DOI: 10.1016/j.neo.2014.10.002
Gobessi S, et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia. 2009;23:686–97. DOI: 10.1038/leu.2008.346
Bojarczuk K, et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127:3192–201. DOI: 10.1182/blood-2015-10-675009
Roberts AW, 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 Off J Am Soc Clin Oncol. 2012;30:488–96. DOI: 10.1200/JCO.2011.34.7898
Klanova, M. & Klener, P. BCL-2 proteins in pathogenesis and therapy of B-cell non-hodgkin lymphomas. Cancers (Basel). 12, (2020).
Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106:2513–9. DOI: 10.1182/blood-2005-04-1678
Yi X, et al. AMG-176, an Mcl-1 antagonist, shows preclinical efficacy in chronic lymphocytic leukemia. Clin cancer Res. 2020;26:3856–67. DOI: 10.1158/1078-0432.CCR-19-1397
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. Off. J. Am. Soc. Clin. Oncol. JCO2000572 (2020). doi: https://doi.org/10.1200/JCO.20.00572
Wei AH, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135:2137–45. DOI: 10.1182/blood.2020004856
DiNardo CD, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135:791–803. DOI: 10.1182/blood.2019003988
Yoshimoto G, et al. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood. 2009;114:5034–43. DOI: 10.1182/blood-2008-12-196055
Breitenbuecher F, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009;113:4063–73. DOI: 10.1182/blood-2007-11-126664
Kaufmann SH, et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood. 1998;91:991–1000. DOI: 10.1182/blood.V91.3.991.991_991_1000
Li X-X, et al. Increased MCL-1 expression predicts poor prognosis and disease recurrence in acute myeloid leukemia. Onco Targets Ther. 2019;12:3295–304. DOI: 10.2147/OTT.S194549
Kuusanmäki H, et al. Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia. Haematologica. 2020;105:708–20. DOI: 10.3324/haematol.2018.214882
Ewald L, Dittmann J, Vogler M, Fulda S. Side-by-side comparison of BH3-mimetics identifies MCL-1 as a key therapeutic target in AML. Cell Death Dis. 2019;10:917. DOI: 10.1038/s41419-019-2156-2
Moujalled DM, et al. Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. Leukemia. 2019;33:905–17. DOI: 10.1038/s41375-018-0261-3
Pan R, et al. Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor (-)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood. 2015;126:363–72. DOI: 10.1182/blood-2014-10-604975
Lin KH, et al. Targeting MCL-1/BCL-XL forestalls the acquisition of resistance to ABT-199 in acute myeloid leukemia. Sci Rep. 2016;6:27696. DOI: 10.1038/srep27696
Fiskus W, et al. Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019;9:4. DOI: 10.1038/s41408-018-0165-5
Stevens BM, et al. PTPN11 mutations confer unique metabolic properties and increase resistance to venetoclax and azacitidine in acute myelogenous leukemia. Blood. 2018;132:909. DOI: 10.1182/blood-2018-99-119806
Chen L, et al. Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition. Leukemia. 2015;29:1290–300. DOI: 10.1038/leu.2015.18
Czabotar PE, et al. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci U S A. 2007;104:6217–22. DOI: 10.1073/pnas.0701297104
Day CL, et al. Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands. J Biol Chem. 2005;280:4738–44. DOI: 10.1074/jbc.M411434200
Soderquist R, Eastman A. BCL2 inhibitors as anticancer drugs: a plethora of misleading BH3 mimetics. Mol Cancer Ther. 2016;15:2011–7. DOI: 10.1158/1535-7163.MCT-16-0031
Gregory GP, et al. CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo. Leukemia. 2015;29:1437–41. DOI: 10.1038/leu.2015.10
Wu X, Luo Q, Liu Z. Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options. Cell Death Dis. 2020;11:556. DOI: 10.1038/s41419-020-02760-y
Szlávik Z, et al. Structure-guided discovery of a selective MCL-1 inhibitor with cellular activity. J Med Chem. 2019;62:6913–24. DOI: 10.1021/acs.jmedchem.9b00134
Brennan MS, et al. Humanized Mcl-1 mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use. Blood. 2018;132:1573–83. DOI: 10.1182/blood-2018-06-859405
Halilovic E, et al. Abstract 4477: MIK665/S64315, a novel Mcl-1 inhibitor, in combination with Bcl-2 inhibitors exhibits strong synergistic antitumor activity in a range of hematologic malignancies. Cancer Res. 2019;79:4477.
Tron AE, et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018;9:5341. DOI: 10.1038/s41467-018-07551-w
Caenepeel S, et al. Abstract 6218: Discovery and preclinical evaluation of AMG 397, a potent, selective and orally bioavailable MCL1 inhibitor. Cancer Res. 2020;80:6218.
Ramsey HE, et al. A Novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia. Cancer Discov. 2018;8:1566–81. DOI: 10.1158/2159-8290.CD-18-0140
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. 2019b;62:3971–88. DOI: 10.1021/acs.jmedchem.8b01991
Lu X, Liu Y-C, Orvig C, Liang H, Chen Z-F. Discovery of β-carboline copper(II) complexes as Mcl-1 inhibitor and in vitro and in vivo activity in cancer models. Eur J Med Chem. 2019;181:111567. DOI: 10.1016/j.ejmech.2019.111567
He Y, et al. Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies. J Hematol Oncol. 2020;13:103. DOI: 10.1186/s13045-020-00924-z
Papatzimas JW, et al. From inhibition to degradation: targeting the antiapoptotic protein myeloid cell leukemia 1 (MCL1). J Med Chem. 2019;62:5522–40. DOI: 10.1021/acs.jmedchem.9b00455
Wang Z, et al. Proteolysis targeting chimeras for the selective degradation of Mcl-1/Bcl-2 derived from nonselective target binding ligands. J Med Chem. 2019;62:8152–63. DOI: 10.1021/acs.jmedchem.9b00919
Spencer, A. et al. 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, e53–e54 (2019).
Certo M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9:351–65. DOI: 10.1016/j.ccr.2006.03.027
Foight GW, Ryan JA, Gullá SV, Letai A, Keating AE. Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells. ACS Chem Biol. 2014;9:1962–8. DOI: 10.1021/cb500340w
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.
