Targeting radioresistance and replication fork stability in prostate cancer.

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ICR Authors

Carreira, Suzanne
 Yuan, Wei
 De Bono, Johann

Authors

Li, X
Baek, G
Carreira, S
Yuan, W
Ma, S
Hofstad, M
Lee, S
Gao, Y
Bertan, C
Fenor de la Maza, MDLD
Alluri, PG
Burma, S
Chen, BP
Raj, GV
de Bono, J
Pommier, Y
Mani, RS

Document Type

Journal Article

Date

2022-05-09

Date Accepted

2022-03-24

Abstract

The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC). We hypothesized novel combinatorial strategies are likely to enhance the efficacy of BETi. By using PCa patient-derived explants and xenograft models, we show that BETi treatment enhanced the efficacy of radiation therapy (RT) and overcame radioresistance. Mechanistically, BETi potentiated the activity of RT by blocking DNA repair. We also report a synergistic relationship between BETi and topoisomerase I (TOP1) inhibitors (TOP1i). We show that the BETi OTX015 synergized with the new class of synthetic noncamptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Mechanistically, BETi potentiated the antitumor activity of TOP1i by disrupting replication fork stability. Longitudinal analysis of patient tumors indicated that TOP1 transcript abundance increased as patients progressed from hormone-sensitive prostate cancer to CRPC. TOP1 was highly expressed in metastatic CRPC, and its expression correlated with the expression of BET family genes. These studies open new avenues for the rational combinatorial treatment of aggressive PCa.

Citation

JCI Insight, 2022, 7 (9), pp. e152955 -

DOI

10.1172/jci.insight.152955

URI

https://repository.icr.ac.uk/handle/internal/5245

Rights

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

Source Title

JCI Insight

Publisher

AMER SOC CLINICAL INVESTIGATION INC

ISSN

2379-3708

eISSN

2379-3708
2379-3708

Collections

Cancer Therapeutics

Research Team

Cancer Biomarkers
PrCa Targeted Therapy

Notes