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

Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-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 their 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 RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4 + and CD8 + T cells and reduces CD4 + and CD8 + regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial ( NCT04524702 ). • Paricalcitol (P) and hydroxychloroquine (H) enhance the efficacy of chemotherapy in PDAC • Adding PH to gemcitabine (G) induces autophagy and its markers in PDAC • scRNA-seq analysis reveals that GPH treatment reduces cancer-associated fibroblasts • GPH treatment increases M1 polarization and CD4 + and CD8 + T cell activation Nagaraju et al. have identified that paricalcitol (P) plus hydroxychloroquine (H) potentiates the efficacy of gemcitabine (G) in PDAC. GPH treatment induces ER stress and autophagy with M1 polarization and T cell activation. These findings in PDAC patient-derived data highlight the potential translational impact of GPH therapy in improving clinical outcomes.