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Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations

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Listed:
  • Richard W. Birkinshaw

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Jia-nan Gong

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Cindy S. Luo

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Daisy Lio

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Christine A. White

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Mary Ann Anderson

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne
    Peter MacCallum Cancer Centre and Royal Melbourne Hospital)

  • Piers Blombery

    (Peter MacCallum Cancer Centre and Royal Melbourne Hospital
    Peter MacCallum Cancer Centre
    University of Melbourne)

  • Guillaume Lessene

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne
    The University of Melbourne)

  • Ian J. Majewski

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Rachel Thijssen

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Andrew W. Roberts

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne
    Peter MacCallum Cancer Centre and Royal Melbourne Hospital
    University of Melbourne)

  • David C. S. Huang

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Peter M. Colman

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Peter E. Czabotar

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

Abstract

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.

Suggested Citation

  • Richard W. Birkinshaw & Jia-nan Gong & Cindy S. Luo & Daisy Lio & Christine A. White & Mary Ann Anderson & Piers Blombery & Guillaume Lessene & Ian J. Majewski & Rachel Thijssen & Andrew W. Roberts & , 2019. "Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10363-1
    DOI: 10.1038/s41467-019-10363-1
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    Cited by:

    1. Hudie Wei & Haolan Wang & Genxin Wang & Lingzhi Qu & Longying Jiang & Shuyan Dai & Xiaojuan Chen & Ye Zhang & Zhuchu Chen & Youjun Li & Ming Guo & Yongheng Chen, 2023. "Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Annabel K. Sangree & Audrey L. Griffith & Zsofia M. Szegletes & Priyanka Roy & Peter C. DeWeirdt & Mudra Hegde & Abby V. McGee & Ruth E. Hanna & John G. Doench, 2022. "Benchmarking of SpCas9 variants enables deeper base editor screens of BRCA1 and BCL2," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Fengwei Li & Junjie Liu & Chao Liu & Ziyan Liu & Xiangda Peng & Yinyue Huang & Xiaoyu Chen & Xiangnan Sun & Sen Wang & Wei Chen & Dan Xiong & Xiaotong Diao & Sheng Wang & Jingjing Zhuang & Chuanliu Wu, 2024. "Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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