Abstract 6159: Transcriptional regulation of DNA damage response and associated inflammatory signaling by CDK7 in prostate cancer

Metastatic prostate cancer (PCa) is incurable and the second leading cause of cancer death among men in the Western world. Although patients initially respond to androgen deprivation therapy (ADT), most eventually develop castration-resistant prostate cancer (CRPC) and metastasize to bone. Second-generation AR signaling inhibitors, such as abiraterone acetate and enzalutamide, have been shown to provide a median survival benefit of 6 to 24 months for metastatic CRPC patients. Therefore, more effective therapies are needed, including novel and innovative therapeutic combination approaches. PARP inhibitors are used primarily in treating patients with DNA damage response (DDR) pathway (e.g. BRCA1/2) mutated cancers because these mutations cause a deficit in homology-directed DNA repair (HDR) that confers sensitivity to these agents. Though BRCA1/2 mutations are relatively rare, genomic defects in other DNA repair genes account for approximately 20% of advanced CRPC. Therefore, PARP inhibitor was recently FDA-approved for metastatic PCa carrying these mutations. However, the rest of the 80% HR-proficient CRPC patients do not benefit from PARPi. Apart from that, prostate tumors are immunologically cold tumors and only 5% of PCa patients respond to immune checkpoint blockers. Using next generation genomics approaches, we have found that inhibiting transcriptional kinase CDK7 in PCa cells creates a BRCA-deficient state (BRCAness) that sensitizes these HR-proficient tumor cells to PARP inhibitors in vitro and in vivo. Mechanistically, knockdown or inhibition of CDK7 led to transcriptional downregulation of DDR genes through loss of Mediator activity along with accumulation of R-loops resulting in the induction of DNA damage, micronuclei formation with consequent activation of cGAS-STING mediated inflammatory signaling, and synergy with anti-PD1 therapy in a syngeneic PCa model in vivo without toxicity. These findings suggest that CDK7 inhibition synergizes with PARP inhibitors and immune checkpoint blockers, offering a promising therapeutic strategy for both HR-proficient and HR-deficient metastatic PCa. This approach has the potential to overcome current limitations of immune checkpoint inhibitors and provides new avenues for targeted combination therapies in advanced PCa treatment. Citation Format: Chandan Kanta Das, Hesham Mohei, Brijesh Kumar Verma, Muzaffer Kassab, Phillip Wulfridge, Sharan Venkatesh, Mohammed Alhusayan, Reyaz ur Rasool, Kavitha Sarma, Roger A. Greenberg, Eric J. Brown, Malay Haldar, Irfan A. Asangani. Transcriptional regulation of DNA damage response and associated inflammatory signaling by CDK7 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6159.