Targeting the SRC/JAK/STAT3 signalling pathway: A novel and promising therapeutic strategy for pancreatic cancer

Abstract

Pancreatic cancer has a 5-year survival of only 8%, and persists as the 4th most common cause of cancer-related death in Western societies. A more tailored treatment approach may be beneficial as the current standard-of-care therapies offer only a modest increase in overall patient survival. Recent large-scale genomic studies have revealed that the SRC/JAK/STAT3 signalling pathway is deregulated in up to 35% of pancreatic cancers, and is yet to be systematically examined in this disease. Consequently, we hypothesised that targeting pancreatic tumours with alterations in the SRC/JAK/STAT3 signalling pathway with JAK and SRC inhibitors represents a promising novel therapeutic strategy for this disease. In this thesis, we use well-annotated patient-derived cell-line models (ICGC), along with cell-lines generated from the aggressive KPC mouse model, to show that the combination of selected JAK and SRC inhibitors is synergistic in cell lines characterised by high phospho-STAT3 expression and P53 mutations. Using 3D in vitro models, including organotypic and organoid models, we show that this therapeutic strategy inhibits the invasive and proliferative capacity of tumour cells, disrupts collagen remodelling and extracellular matrix integrity, interferes with paracrine signalling and has strong immunomodulatory effects. Lastly, we examine the in vivo efficacy of dasatinib and ruxolitinib using a syngeneic KPC mouse model, as well as patient-derived pancreatic tumour models, characterised by high phospho-STAT3 expression and P53 mutations. From these studies we demonstrate that the combination of dasatinib and ruxolitinib significantly inhibited tumour progression, improved survival, delayed the development of metastasis and significantly improved response to standard of care chemotherapy. Furthermore, tumours treated with dasatinib and ruxolitinib displayed decreased collagen deposition and remodelling, and altered immune cell infiltration in the syngeneic setting. Our findings demonstrate the potential for tailored therapeutic strategies involving SRC/JAK/STAT3 inhibition in pancreatic cancer, and suggest that therapeutic efficacy may be the result of targeting both tumour cells and the tumour microenvironment, by decreasing fibrosis and overcoming tumour-induced immunosuppression.