Targeting an RNA polymerase II-associated PHF5A transcriptional subcomplex with a KMT2A-WDR5 inhibitor impairs self-renewal, pluripotency and tumorigenicity of pancreatic cancer stem cells II

Pancreatic cancer remains one of the most aggressive and lethal cancers in humans. It is undeniably known for its notorious resistance to conventional chemotherapeutics which are often associated with a transient response to treatment but rapidly followed by drug resistance and tumor recurrence. Increasing evidence suggests that therapy failure in pancreatic cancer is largely ascribed to the residual subpopulation of undifferentiated cells, known as cancer stem cells (CSCs), which are evolutionary 'fitter' than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are outstandingly critical for tumor relapse as they possess unique 'stem cell-like' features of self-renewal and differentiation which render them capable of regenerating the original tumor. Through the identification of key epigenetic regulators of CSCs phenotypes and functions, this project seeks to gain insight into the molecular mechanisms underlying tumor recurrence and identify novel therapeutic candidates for eliminating CSCs and achieving long-term clinical responses in pancreatic cancer patients. Chromatin immunoprecipitation DNA-sequencing (chIP-seq) for PHF5A and PHF14 in ABCG2+ L3.6pl tumorspheres treated with DMSO (control) and 50 µM MM-102