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<p>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 <i>RB1</i> 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 <i>TP53/CDKN1A</i>-dependent suppression of <i>BIRC5</i> 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 <i>RB1</i> loss, and that pharmacological induction of replication stress may be a broadly applicable approach for sensitizing to BCL-XL inhibitors.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月28日

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  • 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,
  • Juliet Carmichael,
  • Fang Xie,
  • Ines Figueiredo,
  • Lorenzo Buroni,
  • Antje Neeb,
  • Bora Gurel,
  • Nicholas Chevalier,
  • Lisha Brown,
  • Olga Voznesensky,
  • Shao-Yong Chen,
  • Joshua W. Russo,
  • Xin Yuan,
  • Dejan Juric,
  • Himisha Beltran,
  • Johann S. De Bono,
  • Matthew G. Vander Heiden,
  • David J. Einstein,
  • Taru Muranen,
  • Eva Corey,
  • Adam Sharp,
  • Steven P. Balk

摘要

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.