دورية أكاديمية
Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic-Resistant AML and AML Stem Cells.
| العنوان: | Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic-Resistant AML and AML Stem Cells. |
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| المؤلفون: | Carter BZ; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Mak PY; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Tao W; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Zhang Q; Section of Leukemia Biological Research, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ruvolo V; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kuruvilla VM; Section of Leukemia Biological Research, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wang X; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Mak DH; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Battula VL; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Konopleva M; Section of Leukemia Biological Research, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Jabbour EJ; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hughes PE; Oncology Research, Amgen Inc., Thousand Oaks, California., Chen X; Oncology Research, Amgen Inc., Thousand Oaks, California., Morrow PK; Amgen Inc., Thousand Oaks, California., Andreeff M; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2022 Jun 01; Vol. 21 (6), pp. 879-889. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Apoptosis Regulatory Proteins* , Biomimetic Materials*/pharmacology , Leukemia, Myeloid, Acute*/drug therapy , Leukemia, Myeloid, Acute*/metabolism, Animals ; Apoptosis ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Line, Tumor ; Humans ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Proto-Oncogene Proteins c-bcl-2 ; Stem Cells/metabolism ; bcl-2-Associated X Protein/metabolism ; bcl-2-Associated X Protein/pharmacology |
| مستخلص: | MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Cotargeting BCL-2 and MCL-1 was highly synergistic in AML cell lines with intrinsic or acquired resistance to BH3 mimetics or engineered to genetically overexpress BCL-2 or BCL-2A1 or downregulate BAX. The combination effectively eliminated primary AML blasts and stem/progenitor cells resistant to or relapsed after venetoclax-based therapy irrespective of mutations and cytogenetic abnormalities. Venetoclax and AMG176 combination markedly suppressed antiapoptotic BCL-2 proteins and AML stem/progenitor cells and dramatically extended mouse survival (median 336 vs. control 126 days; P < 0.0001) in a patient-derived xenograft (PDX) model developed from a venetoclax/hypomethylating agent therapy-resistant patient with AML. However, decreased BAX levels in the bone marrow residual leukemia cells after 4-week combination treatment may represent a resistance mechanism that contributed to their survival. Enhanced antileukemia activity was also observed in a PDX model of monocytic AML, known to be resistant to venetoclax therapy. Our results support codependence on multiple antiapoptotic BCL-2 proteins and suppression of BAX as mechanisms of AML resistance to individual BH3 mimetics. Cotargeting of MCL-1 and BCL-2 eliminates otherwise apoptosis-resistant cells. (©2022 American Association for Cancer Research.) |
| References: | Cancer Discov. 2014 Mar;4(3):362-75. (PMID: 24346116) Cancer Cell. 2017 Dec 11;32(6):748-760.e6. (PMID: 29232553) Cancer Discov. 2019 Jul;9(7):890-909. (PMID: 31048321) Lancet Oncol. 2018 Feb;19(2):216-228. (PMID: 29339097) Nat Commun. 2018 Aug 29;9(1):3513. (PMID: 30158527) Cancer Discov. 2016 Oct;6(10):1106-1117. (PMID: 27520294) Adv Enzyme Regul. 1984;22:27-55. (PMID: 6382953) Cancer Res. 2002 Jul 1;62(13):3603-8. (PMID: 12097260) Oncogene. 2018 Apr;37(14):1830-1844. (PMID: 29353886) Cancer Discov. 2018 Dec;8(12):1582-1597. (PMID: 30254093) Nat Commun. 2018 Dec 17;9(1):5341. (PMID: 30559424) Leukemia. 2019 Apr;33(4):905-917. (PMID: 30214012) Haematologica. 2020 Dec 23;107(1):58-76. (PMID: 33353284) PLoS Comput Biol. 2016 Sep 23;12(9):e1005112. (PMID: 27662185) Cancer Discov. 2019 Jul;9(7):910-925. (PMID: 31048320) Mol Cancer Ther. 2020 Aug;19(8):1636-1648. (PMID: 32404407) Biotech Histochem. 2003 Oct;78(5):261-70. (PMID: 14989644) J Clin Invest. 2013 Jun;123(6):2395-407. (PMID: 23676502) Blood. 1998 Feb 1;91(3):991-1000. (PMID: 9446661) Cancer Discov. 2018 Dec;8(12):1566-1581. (PMID: 30185627) Blood. 2020 Mar 5;135(10):773-777. (PMID: 31951646) Leukemia. 2017 Nov;31(11):2336-2346. (PMID: 28280274) Nucleic Acids Res. 2009 Jan;37(Database issue):D925-32. (PMID: 18927105) Blood. 2010 Apr 22;115(16):3304-13. (PMID: 20197552) Cancer Cell. 2019 Oct 14;36(4):369-384.e13. (PMID: 31543463) Cancer Discov. 2019 Mar;9(3):342-353. (PMID: 30514704) Blood. 2019 Jan 3;133(1):7-17. (PMID: 30361262) Cancer Discov. 2020 Apr;10(4):536-551. (PMID: 31974170) Cancer. 2012 Feb 15;118(4):1023-31. (PMID: 21761401) Blood. 2020 Mar 12;135(11):791-803. (PMID: 31932844) Cancer Cell. 2019 May 13;35(5):752-766.e9. (PMID: 31085176) |
| معلومات مُعتمدة: | P30 CA016672 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Apoptosis Regulatory Proteins) 0 (Bridged Bicyclo Compounds, Heterocyclic) 0 (Myeloid Cell Leukemia Sequence 1 Protein) 0 (Proto-Oncogene Proteins c-bcl-2) 0 (bcl-2-Associated X Protein) |
| تواريخ الأحداث: | Date Created: 20220401 Date Completed: 20220602 Latest Revision: 20221202 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9167707 |
| DOI: | 10.1158/1535-7163.MCT-21-0690 |
| PMID: | 35364607 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
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| DOI: | 10.1158/1535-7163.MCT-21-0690 |