title: Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells.
abstract: The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-x(L), and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-x(L) predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-x(L) or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-x(L)/Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Delphine
authors.initials: D
authors.lastname: Mérino
authors.forename: Seong L
authors.initials: SL
authors.lastname: Khaw
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Belmont
authors.forename: Chihunt
authors.initials: C
authors.lastname: Wong
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Mikara
authors.initials: M
authors.lastname: Robati
authors.forename: Belinda
authors.initials: B
authors.lastname: Phipson
authors.forename: Walter D
authors.initials: WD
authors.lastname: Fairlie
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.forename: Kirsteen J
authors.initials: KJ
authors.lastname: Campbell
authors.forename: Cassandra J
authors.initials: CJ
authors.lastname: Vandenberg
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cory
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Ludlam
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C491073:BCL2L2 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D050505:Mutant Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D005047:Etoposide; C528561:navitoclax