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BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress

Author

Listed:
  • Andreas Varkaris

    (Harvard Medical School
    Harvard Medical School)

  • Keshan Wang

    (Harvard Medical School
    Huazhong University of Science and Technology)

  • Mannan Nouri

    (Harvard Medical School)

  • Nina Kozlova

    (Harvard Medical School)

  • Daniel R. Schmidt

    (Harvard Medical School
    Massachusetts Institute of Technology)

  • Anastasia Stavridi

    (Harvard Medical School)

  • Seiji Arai

    (Harvard Medical School)

  • Nicholas Ambrosio

    (Harvard Medical School)

  • Larysa Poluben

    (Harvard Medical School)

  • Juan M. Jimenez-Vacas

    (Royal Marsden NHS Foundation Trust)

  • Daniel Westaby

    (Royal Marsden NHS Foundation Trust)

  • Juliet Carmichael

    (Royal Marsden NHS Foundation Trust)

  • Fang Xie

    (Harvard Medical School)

  • Ines Figueiredo

    (Royal Marsden NHS Foundation Trust)

  • Lorenzo Buroni

    (Royal Marsden NHS Foundation Trust)

  • Antje Neeb

    (Royal Marsden NHS Foundation Trust)

  • Bora Gurel

    (Royal Marsden NHS Foundation Trust)

  • Nicholas Chevalier

    (Harvard Medical School)

  • Lisha Brown

    (University of Washington)

  • Olga Voznesensky

    (Harvard Medical School)

  • Shao-Yong Chen

    (Harvard Medical School)

  • Joshua W. Russo

    (Harvard Medical School)

  • Xin Yuan

    (Harvard Medical School)

  • Dejan Juric

    (Harvard Medical School)

  • Himisha Beltran

    (Dana-Farber Cancer Institute)

  • Johann S. Bono

    (Royal Marsden NHS Foundation Trust)

  • Matthew G. Heiden

    (Massachusetts Institute of Technology
    Dana-Farber Cancer Institute)

  • David J. Einstein

    (Harvard Medical School)

  • Taru Muranen

    (Harvard Medical School)

  • Eva Corey

    (University of Washington)

  • Adam Sharp

    (Royal Marsden NHS Foundation Trust)

  • Steven P. Balk

    (Harvard Medical School)

Abstract

BH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1 have limited activity in solid tumors. Through assessment of xenograft-derived 3D prostate cancer models and cell lines we find that tumors with RB1 loss are sensitive to BCL-XL inhibition. In parallel, drug screening demonstrates that disruption of nucleotide pools by agents including thymidylate synthase inhibitors sensitizes to BCL-XL inhibition, together indicating that replication stress increases dependence on BCL-XL. Mechanistically we establish that replication stress sensitizes to BCL-XL inhibition through TP53/CDKN1A-dependent suppression of BIRC5 expression. Therapy with a BCL-2/BCL-XL inhibitor (navitoclax) in combination with thymidylate synthase inhibitors (raltitrexed or capecitabine) causes marked and prolonged tumor regression in prostate and breast cancer xenograft models. These findings indicate that BCL-XL inhibitors may be effective as single agents in a subset of solid tumors with RB1 loss, and that pharmacological induction of replication stress may be a broadly applicable approach for sensitizing to BCL-XL inhibitors.

Suggested Citation

  • Andreas Varkaris & Keshan Wang & Mannan Nouri & Nina Kozlova & Daniel R. Schmidt & Anastasia Stavridi & Seiji Arai & Nicholas Ambrosio & Larysa Poluben & Juan M. Jimenez-Vacas & Daniel Westaby & Julie, 2025. "BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60238-x
    DOI: 10.1038/s41467-025-60238-x
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    References listed on IDEAS

    as
    1. Tilman Oltersdorf & Steven W. Elmore & Alexander R. Shoemaker & Robert C. Armstrong & David J. Augeri & Barbara A. Belli & Milan Bruncko & Thomas L. Deckwerth & Jurgen Dinges & Philip J. Hajduk & Mary, 2005. "An inhibitor of Bcl-2 family proteins induces regression of solid tumours," Nature, Nature, vol. 435(7042), pages 677-681, June.
    2. 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.
    Full references (including those not matched with items on IDEAS)

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