Targeting radioresistance and replication fork stability in prostate cancer
Xiangyi Li, … , Yves Pommier, Ram S. Mani
Xiangyi Li, … , Yves Pommier, Ram S. Mani
Published March 29, 2022
Citation Information: JCI Insight. 2022;7(9):e152955. https://doi.org/10.1172/jci.insight.152955.
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Research Article Oncology

Targeting radioresistance and replication fork stability in prostate cancer

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.

Authors

Xiangyi Li, GuemHee Baek, Suzanne Carreira, Wei Yuan, Shihong Ma, Mia Hofstad, Sora Lee, Yunpeng Gao, Claudia Bertan, Maria de los Dolores Fenor de la Maza, Prasanna G. Alluri, Sandeep Burma, Benjamin P.C. Chen, Ganesh V. Raj, Johann de Bono, Yves Pommier, Ram S. Mani

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Figure 5

OTX015 potentiates the antitumor activity of LMP400 in subcutaneous 22Rv1 and DU145 tumor xenografts.

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OTX015 potentiates the antitumor activity of LMP400 in subcutaneous 22Rv...
(A) Subcutaneous tumor xenograft treatment schematic. OTX015 dose: 100 mg/kg, oral gavage, 1 dosage per day; LMP400 dose: 10 mg/kg, IP, once per day. Xenograft tumor-bearing mice were continuously treated (6-day-on/1-day-off cycle) with vehicle or LMP400 or OTX015 or LMP400 + OTX015 until experiment termination. (B) Left panel, growth of 22Rv1 tumor xenografts with indicated treatments. Black arrow indicates treatment start point. The P values were obtained from unpaired 2-tailed Student’s t test. The P values were adjusted by Benjamini-Hochberg procedure for multiple comparisons. n ≥ 5 mice per group. Means ± SEM. Note that half of the error bars are shown here to facilitate clear view. Right panel, measurement of mice body weight. (C) Representative images of mice from all treatment arms. The vertical red lines separate individual images. Color bars on top represent the treatment groups. The number of days inside of parentheses indicates the total time from the start of treatment to experiment termination. The images were obtained on the day of experiment termination. (D) Same as B but with DU145 tumor xenografts. (E) Same as C but with DU145 tumor xenografts. The P values are listed in Supplemental Tables 5 and 6.