title: Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.
abstract: The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.
authors: AbbVie Inc., North Chicago, IL 60064, USA. joel.leverson@abbvie.com.
authors: Joel D
authors: JD
authors: Leverson
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Darren C
authors: DC
authors: Phillips
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Michael J
authors: MJ
authors: Mitten
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Erwin R
authors: ER
authors: Boghaert
authors: Genentech Inc., South San Francisco, CA 94080, USA.
authors: Dolores
authors: D
authors: Diaz
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Stephen K
authors: SK
authors: Tahir
authors: Genentech Inc., South San Francisco, CA 94080, USA.
authors: Lisa D
authors: LD
authors: Belmont
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Paul
authors: P
authors: Nimmer
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Yu
authors: Y
authors: Xiao
authors: Genentech Inc., South San Francisco, CA 94080, USA.
authors: Xiaoju Max
authors: XM
authors: Ma
authors: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Kym N
authors: KN
authors: Lowes
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Peter
authors: P
authors: Kovar
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Jun
authors: J
authors: Chen
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Sha
authors: S
authors: Jin
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Morey
authors: M
authors: Smith
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: John
authors: J
authors: Xue
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Haichao
authors: H
authors: Zhang
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Anatol
authors: A
authors: Oleksijew
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Terrance J
authors: TJ
authors: Magoc
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Kedar S
authors: KS
authors: Vaidya
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Daniel H
authors: DH
authors: Albert
authors: Genentech Inc., South San Francisco, CA 94080, USA.
authors: Jacqueline M
authors: JM
authors: Tarrant
authors: Genentech Inc., South San Francisco, CA 94080, USA.
authors: Nghi
authors: N
authors: La
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Le
authors: L
authors: Wang
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Zhi-Fu
authors: ZF
authors: Tao
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Michael D
authors: MD
authors: Wendt
authors: Genentech Inc., South San Francisco, CA 94080, USA.
authors: Deepak
authors: D
authors: Sampath
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Saul H
authors: SH
authors: Rosenberg
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Chris
authors: C
authors: Tse
authors: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: David C S
authors: DC
authors: Huang
authors: Genentech Inc., South San Francisco, CA 94080, USA.
authors: Wayne J
authors: WJ
authors: Fairbrother
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Steven W
authors: SW
authors: Elmore
authors: AbbVie Inc., North Chicago, IL 60064, USA.
authors: Andrew J
authors: AJ
authors: Souers
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D052160:Benzothiazoles / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival; D000077143:Docetaxel; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use; D043823:Taxoids / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C000603579:A-1155463; C000603580:A-1331852; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D052160:Benzothiazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007546:Isoquinolines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D043823:Taxoids; D051020:bcl-X Protein; D000077143:Docetaxel; C579720:venetoclax; C528561:navitoclax