Mechanism of Enhancing Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma with Paricalcitol and Hydroxychloroquine: A Single Cell RNA Sequencing - Part3

Pancreatic ductal adenocarcinoma (PDAC) boasts a dismal five-year survival rate of less than 15%, mainly due to therapy resistance. Recent studies have highlighted hydroxychloroquine (H) and paricalcitol (P), reducing stromal density and enhancing PDAC sensitivity to chemotherapy. This investigation aimed to elucidate the molecular impacts of combining H and P, focusing on their ability to sensitize PDAC to chemotherapy. In vitro and in vivo experiments demonstrated that the HP combination significantly (p<0.001) enhanced gemcitabine (G) effects, validated in orthotopic mouse models and patient-derived xenografts (PDX). Mechanistically, GPH induced cell death via the vitamin D receptor pathway upregulated autophagy and ER stress-related transcripts and suppressed mTOR signaling. Single-cell (sc) RNAseq analyses showed GPH increased quiescent cancer associated fibroblasts and reduced autophagy related transcripts. GPH treatment modulated T-cell populations favoring antitumor immunity. Findings from clinical trial patient biopsies underscored these effects, highlighting GPH's potential as a therapeutic adjunct in PDAC management (NCT04524702).