Repurposing of valproic acid and simvastatin to boost first-line chemotherapy in pancreatic cancer via TGF-β, EMT and YAP modulation.

Pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge owing to its aggressive nature and limited response to conventional chemotherapy, with a median progression-free survival of seven months using the current first-line therapy. To address this urgent therapeutic gap, we propose an innovative drug repurposing strategy that combines valproic acid (VPA), a histone deacetylase inhibitor (HDACi), and simvastatin (SIM), a cholesterol-lowering drug, with both well-characterized and clinically approved agents. Among the multiple HDACi/statin combinations screened across human and murine PDAC models, VPA/SIM emerged as the most synergistic, demonstrating robust antiproliferative and pro-apoptotic effects in 2D and 3D co-culture systems and patient-derived models. Notably, VPA/SIM enhanced the efficacy of subtherapeutic GEM/TAX doses and significantly suppressed tumor growth in vitro in both human and murine PDAC models, as well as in vivo in both heterotopic and orthotopic PDAC xenografts. The antitumor potential of VPA/SIM combined with GEM/TAX was validated using the REMEDi4ALL repurposing platform. Mechanistically, integrated transcriptomic and proteomic studies have highlighted TGF-β and YAP as key mediators of the response, strongly associated with epithelial-to-mesenchymal transition (EMT) and other chemo-resistance-related pathways. OverallThese data underline the relevance of a drug repurposing strategy to improve the prognosis in a high-mortality neoplasm such as PDAC, exploiting low-risk, economically sustainable interventions that deserve clinical evaluation.