Dual inhibition of FACT and RRM2 suppresses the progression of pancreatic ductal adenocarcinoma driven by the oncohistone H2BG53D

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal cancer with frequent genetic mutations. We previously reported the identification of the histone H2BG53-to-D mutation in PDAC patients and revealed that the mutation destabilizes nucleosomes and promotes cell migration. However, how H2BG53D impacts chromatin and the significance in PDAC development remain largely unknown. Using the genetically engineered mouse models, we demonstrate that H2BG53D accelerates PDAC initiation and metastasis. Moreover, H2BG53D mutation elevates the interaction between nucleosomes and the Facilitates Chromatin Transcription (FACT) complex. FACT depletion reverses transcriptional changes and oncogenic effects induced by H2BG53D mutation. In search of a novel therapeutic strategy for H2BG53D-PDAC, our genome-wide CRISPR/Cas9 screen identified Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) as a druggable target. Remarkably, dual inhibition of RRM2 and FACT exhibits potent cytotoxic effects on PDAC cells in vitro and significantly prolongs the survival of H2BG53D-PDAC mice. This study deciphers the roles and mechanisms of H2BG53D in PDAC progression and proposes a promising therapeutic strategy for this aggressive cancer.