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Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Author

Listed:
  • Jennifer Y. Ge

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Shaokun Shu

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Peking University Cancer Hospital and Institute)

  • Mijung Kwon

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Ewha Womans University)

  • Bojana Jovanović

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Eli and Edythe L. Broad Institute)

  • Katherine Murphy

    (Dana-Farber Cancer Institute)

  • Anushree Gulvady

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Anne Fassl

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Anne Trinh

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Yanan Kuang

    (Dana-Farber Cancer Institute)

  • Grace A. Heavey

    (Dana-Farber Cancer Institute)

  • Adrienne Luoma

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Cloud Paweletz

    (Dana-Farber Cancer Institute)

  • Aaron R. Thorner

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Kai W. Wucherpfennig

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Harvard Medical School)

  • Jun Qi

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Myles Brown

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Piotr Sicinski

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Thomas O. McDonald

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard T. H. Chan School of Public Health
    Harvard University)

  • David Pellman

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Franziska Michor

    (Dana-Farber Cancer Institute
    Eli and Edythe L. Broad Institute
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Kornelia Polyak

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Eli and Edythe L. Broad Institute
    Harvard Medical School)

Abstract

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.

Suggested Citation

  • Jennifer Y. Ge & Shaokun Shu & Mijung Kwon & Bojana Jovanović & Katherine Murphy & Anushree Gulvady & Anne Fassl & Anne Trinh & Yanan Kuang & Grace A. Heavey & Adrienne Luoma & Cloud Paweletz & Aaron , 2020. "Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16170-3
    DOI: 10.1038/s41467-020-16170-3
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