Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion

KRAS is the most commonly mutated oncogene in human cancer and mutant KRAS is responsible for over 90% of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer. Here, we show that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult pancreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin, thereby leading to aberrant R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We go on to demonstrate that the global hyperactivation of enhancers driven by Kras signaling during tumorigenesis underlies the specific demand for PAF1C by cancer cells. Our work provides novel insights in how enhancer transcription hyperactivation causes general transcription factor addiction during tumorigenesis.