2. Academic Validation
  3. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy

Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy

  • Sci Transl Med. 2015 Mar 18;7(279):279ra40. doi: 10.1126/scitranslmed.aaa4642.
Joel D Leverson 1,  Darren C Phillips 2,  Michael J Mitten 2,  Erwin R Boghaert 2,  Dolores Diaz 3,  Stephen K Tahir 2,  Lisa D Belmont 3,  Paul Nimmer 2,  Yu Xiao 2,  Xiaoju Max Ma 3,  Kym N Lowes 4,  Peter Kovar 2,  Jun Chen 2,  Sha Jin 2,  Morey Smith 2,  John Xue 2,  Haichao Zhang 2,  Anatol Oleksijew 2,  Terrance J Magoc 2,  Kedar S Vaidya 2,  Daniel H Albert 2,  Jacqueline M Tarrant 3,  Nghi La 3,  Le Wang 2,  Zhi-Fu Tao 2,  Michael D Wendt 2,  Deepak Sampath 3,  Saul H Rosenberg 2,  Chris Tse 2,  David C S Huang 4,  Wayne J Fairbrother 3,  Steven W Elmore 2,  Andrew J Souers 2
Affiliations

Affiliations

  • 1 AbbVie Inc., North Chicago, IL 60064, USA. joel.leverson@abbvie.com.
  • 2 AbbVie Inc., North Chicago, IL 60064, USA.
  • 3 Genentech Inc., South San Francisco, CA 94080, USA.
  • 4 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
PMID: 25787766 DOI: 10.1126/scitranslmed.aaa4642
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.

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