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

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

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...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-05-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-60238-x
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Summary: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.
ISSN:2041-1723

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