Abstract B073: Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair

Abstract

Abstract Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen-deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in PC, and if Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet assay and clonogenic survival assay, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end-joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors, and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not affecting radiation sensitivity of the neighboring tissues. Conclusion: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Citation Format: Cristina Maranto, Vindhya Udhane, Ayush Dagvadorj, David T. Hoang, Lei Gu, Vitali Alexeev, Kareem Malas, Karmel Cardenas, Mateusz Koptyra, Jonathan R. Brody, Ulrich Rodeck, Carmen Bergom, Ken A. Iczkowski, Ken Jacobsohn, William See, Sara M. Schmitt, Marja T. Nevalainen. Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B073.