BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress
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.
Article Details
Authors (32)
Andreas Varkaris
Keshan Wang
Mannan Nouri
Nina Kozlova
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Daniel R. Schmidt
National Institute of Standards and Technology
Anastasia Stavridi
Seiji Arai
Nicholas Ambrosio
Larysa Poluben
Juan M. Jiménez-Vacas
Daniel Westaby
Juliet Carmichael
Fang Xie
CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences
Ines Figueiredo
Lorenzo Buroni
Antje Neeb
Bora Gurel
Nicholas Chevalier
Lisha Brown
Olga Voznesensky
Shao-Yong Chen
Joshua W. Russo
Xin Yuan
Dejan Juric
Mass General Cancer Center, Department of Medicine, Harvard Medical School, Boston
Himisha Beltran
Johann S. de Bono
Matthew G. Vander Heiden
David J. Einstein
Taru Muranen
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Eva Corey
Department of Urology, University of Washington
Adam Sharp
Steven P. Balk
Department of Medicine, Beth Israel Deaconess Medical Center