Abstract A057: Therapeutic efficacy of selective CDK7 inhibition in pancreatic cancer mediated by induction of R-loop formation, DNA replication stress and genomic instability

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with 5-year overall survival of less than 10% and few effective therapies. Here, we demonstrate that cyclin dependent kinase 7 (CDK7) is essential for the proliferation and viability of PDAC cells by showing potent anti-tumor efficacy for the CDK7-specific inhibitor YKL-5-124 in preclinical PDAC models. Selective CDK7 inhibition leads to G2/M cell cycle arrest and apoptosis in PDAC, while mediating a more modest transcriptional response compared with multi-targeted CDK7 inhibitors. YKL-5-124 treatment impairs DNA damage repair pathways in PDAC cells and evokes genomic instability by inducing R-loop formation and DNA replication stress in telomeric regions leading to chromosomal bridging and micronuclei formation. Furthermore, we demonstrate that selective CDK7 inhibition has in vitro and in vivo combinatorial efficacy with gemcitabine chemotherapy through pronounced induction of replication stress and apoptosis. Collectively, these findings support selective CDK7 inhibition as a promising therapeutic strategy for PDAC. Citation Format: Annan Yang, Jie Jiang, Ziyue Li, Kevin S. Kapner, Hanrong Feng, Kristen E. Lowder, Miljan Kuljanin, Whiteny Johnson, Giselle Uribe, Jasper E. Neggers, Shengwu Liu, Tinghu Zhang, James Decaprio, Ewa Sicinska, Brian M. Wolpin, Nicholas P. Kwiatkowski, Stephanie K. Dougan, Joseph D. Mancias, Nathanael S. Gray, Andrew J. Aguirre. Therapeutic efficacy of selective CDK7 inhibition in pancreatic cancer mediated by induction of R-loop formation, DNA replication stress and genomic instability [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A057.