Therapeutic efficacy of CDK7 inhibition in pancreatic cancer through proliferation arrest and inducing replication stress [PDX]

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with 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 CDK7/12/13 inhibitors. YKL-5-124 treatment impairs DNA damage repair (DDR) 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. Overall design: Examination of the Pancreatic cell line PATU-8988T treated with DMSO vs CDK7 inhibitors (THZ1 or YKL-5-124) for 4-hour or 24-hour.