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

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. Bono, Matthew G. Heiden, David J. Einstein, Taru Muranen, Eva Corey, Adam Sharp and Steven P. Balk ()
Additional contact information
Andreas Varkaris: Harvard Medical School
Keshan Wang: Harvard Medical School
Mannan Nouri: Harvard Medical School
Nina Kozlova: Harvard Medical School
Daniel R. Schmidt: Harvard Medical School
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60238-x

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