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Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity

Author

Listed:
  • Ryan S. Soderquist

    (Duke University)

  • Lorin Crawford

    (Duke University
    Brown University School of Public Health)

  • Esther Liu

    (Duke University)

  • Min Lu

    (Duke University)

  • Anika Agarwal

    (Duke University)

  • Gray R. Anderson

    (Duke University)

  • Kevin H. Lin

    (Duke University)

  • Peter S. Winter

    (Duke University)

  • Merve Cakir

    (Duke University)

  • Kris C. Wood

    (Duke University)

Abstract

While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-XL, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-XL+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-XL, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics.

Suggested Citation

  • Ryan S. Soderquist & Lorin Crawford & Esther Liu & Min Lu & Anika Agarwal & Gray R. Anderson & Kevin H. Lin & Peter S. Winter & Merve Cakir & Kris C. Wood, 2018. "Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05815-z
    DOI: 10.1038/s41467-018-05815-z
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