Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine

Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) five-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and its potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNAseq analyses reveal that GPH treatment upregulates autophagy and ER stress-related transcripts. GPH treatment decreases the number of Ki67, FAP, and alpha-SMA-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization, CD4+, and CD8+ T-cells and reduces the CD4+ and CD8+ Tregs. These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial (NCT04524702). Overall design: This investigation aims to elucidate the molecular properties of the hydroxychloroquine (H) and paricalcitol (P) combination and its potential in sensitizing pancreatic ductal adenocarcinoma (PDAC) to gemcitabine (G). Proteomic and single-cell RNAseq analyses will reveal that GPH treatment upregulates autophagy and ER stress-related transcripts.