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. Jiménez-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
2025-05-28
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.