Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells

Merino, D; Khaw, SL; Glaser, SP; Anderson, DJ; Belmont, LD; Wong, CH; Yue, P; Robati, M; Phipson, B; Fairlie, WD; Lee, EF; Campbell, KJ; Vandenberg, CJ; Cory, S; Roberts, AW; Ludlam, MJC; Huang, DCS; Bouillet, P

Author(s): Merino, D; Khaw, SL; Glaser, SP; Anderson, DJ; Belmont, LD; Wong, CH; Yue, P; Robati, M; Phipson, B; Fairlie, WD; Lee, EF; Campbell, KJ; Vandenberg, CJ; Cory, S; Roberts, AW; Ludlam, MJC; Huang, DCS; Bouillet, P;
Details: Publication Year 2012-06-14,Volume 119,Issue #24,Page 5807-5816
Journal Title: BLOOD
Publication Type: Journal Article
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. (Blood. 2012; 119(24):5807-5816)
Publisher: AMER SOC HEMATOLOGY
Keywords: CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; BH3 MIMETIC ABT-737; FAMILY-MEMBERS; APOPTOTIC RESPONSES; ANTAGONIST ABT-737; INHIBITOR ABT-737; MULTIPLE-MYELOMA; LUNG-CANCER; EXPRESSION
Research Division(s): Molecular Genetics Of Cancer; Cancer And Haematology; Chemical Biology; Structural Biology
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382939/
Publisher's Version: https://doi.org/10.1182/blood-2011-12-400929

Creation Date: 2012-06-14 12:00:00