Paricalcitol and hydroxychloroquine modulates extracellular matrix and enhance chemotherapy efficacy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and limited therapeutic options. In a previous publication, our group defined some of the mechanisms that vitamin D analogue paricalcitol (P) and hydroxychloroquine (H) potentiated the effects of gemcitabine-based chemotherapy in PDAC. Based on this, we hypothesized that the mechanisms of potentiation of 5-Fluorouracil (5FU) and oxaliplatin-based chemotherapy by PH may include different pathways than what was seen with gemcitabine-based therapy. Using MIA PaCa-2, HPAC and KPC cell lines, the combination of PH significantly increased the cell death, apoptosis, and S-phase cell cycle arrest. In vivo, the combination therapy inhibited PDAC growth and altered the immune landscape by activating T and NK cells. Proteomic analysis revealed that, significant reduction in ECM proteins, specifically integrin beta-4 (ITGB4) which was also seen with gemcitabine. Furthermore, genetic knockdown of ITGB4 suggested that the ECM inhibiti