PO-046 Dual inhibition of JAK and Src: a novel and promising therapeutic combination for pancreatic cancer

Introduction Pancreatic cancer (PC) has a 5 year survival of only 6%, 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 patient overall. Recent large-scale genomic studies have revealed that the Src/JAK/STAT3 signalling pathway is deregulated in up to 35% of PC, and is yet to be systematically examined in this disease. Consequently, we hypothesised that targeting pancreatic tumours with activated JAK/STAT3 signalling with selective JAK1/JAK2 or JAK3 inhibitors and an Src inhibitor represents a promising novel therapeutic strategy for this disease. Material and methods We utilised well-annotated patient-derived cell-line models (ICGC), along with cell-lines generated from the aggressive the KPC mouse model. Using these pre-clinical models we assessed the in vitro efficacy of therapeutic strategies involving Src/JAK/STAT3 inhibition, using cell proliferation assays, 2D-drug synergy screens, and 3D organotypic invasion assays. Extracellular matrix integrity post-treatment was assessed using second-harmonic generation (SHG) imaging and picrosirius staining. To examine in vivo efficacy, we utilised a syngeneic KPC mouse model, and performed both orthotopic and subcutaneous studies. Results and discussions We show that selected JAK and Src-inhibitors inhibit cell proliferation in candidate PDCLs and KPC lines, characterised by activated Src/JAK/STAT3 signalling, with combination therapy being synergistic in the majority of these cell-lines. Cell invasion was significantly inhibited in organotypic matrices, and there was decreased collagen contractility, and reduced fibrillar collagen coverage. We also demonstrate the in vivo efficacy of these therapies, and show their ability to reduce regulatory T-cells, MDSCs and tumour-associated macrophages. Conclusion Our findings demonstrate the potential for tailored therapeutic strategies involving Src/JAK/STAT3 inhibition in PC, and suggest that therapeutic efficacy may be the result of targeting both tumour cells and the tumour microenvironment, as well as by overcoming tumour-induced immunosuppression.