Sensitivity of pancreatic adenocarcinoma cells to blockade of post-initiation CDK-dependent Pol II transcription cycle checkpoints

Abstract

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity, with oncogenic KRAS/MAPK/ERK signalling arising from activating KRAS mutations being the key feature of this malignancy. Dysregulation of RNA polymerase II (Pol II)-dependent transcription is a universal hallmark of cancers including PDAC, with aberrant gene expression programs driving tumorigenesis and influencing therapy response. Pol II progression through multiple transcription cycle checkpoints depends on transcriptional cyclin-dependent-kinases (tCDKs), and targeted inhibition of distinct tCDKs has been shown to be a promising anti-cancer strategy. In this study we profile biological and molecular PDAC cell responses to selective blockade of tCDK kinase activity at all Pol II transcription cycle checkpoints, alone and in combination with inhibitors of mutant-KRAS or MEK. We identify post-transcription-initiation checkpoints controlled by CDK9, CDK11, and CDK12/13 as critical for nascent gene expression and cell proliferation in PDAC. However, while dual targeting of tCDK and KRAS/MAPK/ERK networks amplifies transcriptomic phenotypes this resulted in limited cooperative therapeutic impacts.