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 H2BG53D mutation and revealed that this mutation destabilizes nucleosomes and promotes cell migration. However, how H2BG53D impacts chromatin and its significance in PDAC development remain unknown. Using genetically engineered mouse models, we demonstrate that H2BG53D promotes PDAC initiation and metastasis. Moreover, H2BG53D elevates the interaction between nucleosomes and the facilitates chromatin transcription (FACT) complex. FACT depletion reverses transcriptional changes and oncogenic effects induced by H2BG53D. In search of therapeutic strategies, our genome-wide CRISPR-Cas9 screen identified ribonucleotide reductase regulatory subunit M2 (RRM2) as a druggable target for H2BG53D-PDAC. Remarkably, dual inhibition of RRM2 and FACT markedly inhibits PDAC development and significantly prolongs the survival of H2BG53D-PDAC mice. This study deciphers the roles and mechanisms of H2BG53D in PDAC and proposes a promising therapeutic strategy for this aggressive cancer. © 2025 The Author(s).