title: Pathways and mechanisms of venetoclax resistance.
abstract: The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XLand MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current 'BH3 profiling' techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-XLand MCL-1 is eagerly awaited.
authors.affiliation: a Department of Leukemia , University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Bose
authors.affiliation: a Department of Leukemia , University of Texas MD Anderson Cancer Center , Houston , TX , USA.|b Department of Experimental Therapeutics , University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.affiliation: a Department of Leukemia , University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D032701:Biomimetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D019086:Bridged Bicyclo Compounds, Heterocyclic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C579720:venetoclax
keywords: BCL-2; BCL-XL; MCL-1; Venetoclax; rational combinations; resistance