Poster Presentation 30th Lorne Cancer Conference 2018

Dual inhibition of JAK and Src: A novel and promising therapeutic combination for pancreatic cancer (#240)

Ashleigh L Parkin 1 , Angela Steinmann 1 , Danielle Froio 1 , Rhys Stark 1 , Ali Drury 1 , Kendelle Murphy 1 , Niantao Deng 1 , Jaswinder Samra 2 , Anthony Gill 1 3 4 5 , Paul Timpson 1 , Marina Pajic 1
  1. The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Department of Surgery, Royal North Shore Hospital, Sydney
  3. Sydney Medical School, University of Sydney, Sydney
  4. Department of Anatomical Pathology, Royal North Shore Hospital,, Sydney
  5. Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney

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. 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 hypothesized 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.

Materials and methods: We utilized well-annotated patient-derived cell-line models (ICGC), along with cell-lines generated from the aggressive 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. We also used the syngeneic, orthotopic KPC mouse model to examine effects on immune-cell infiltrate.

Results: We show that selected JAK and Src-inhibitors inhibit cell proliferation in candidate PDCLs and KPC lines, characterized 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 show that these therapies 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.