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

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Embargo End Date

ICR Authors

Carmichael, Juliet
 Figueiredo, Ines
 Gurel, Bora
 De Bono, Johann

Authors

Varkaris, A
Wang, K
Nouri, M
Kozlova, N
Schmidt, DR
Stavridi, A
Arai, S
Ambrosio, N
Poluben, L
Jimenez-Vacas, JM
Westaby, D
Carmichael, J
Xie, F
Figueiredo, I
Buroni, L
Neeb, A
Gurel, B
Chevalier, N
Brown, L
Voznesensky, O
Chen, S-Y
Russo, JW
Yuan, X
Juric, D
Beltran, H
De Bono, JS
Vander Heiden, MG
Einstein, DJ
Muranen, T
Corey, E
Sharp, A
Balk, SP

Document Type

Journal Article

Date

2025-05-28

Date Accepted

2025-05-19

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.

Citation

Nature Communications, 2025, 16 (1), pp. 4931 -

DOI

10.1038/s41467-025-60238-x

URI

https://repository.icr.ac.uk/handle/internal/6718

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Nature Communications

Publisher

NATURE PORTFOLIO

ISSN

2041-1723

eISSN

2041-1723

Collections

Cancer Therapeutics

Research Team

Cancer Biomarkers
PrCa Targeted Therapy

Notes