Download files
Abstract
Pancreatic cancer (PC) still remains one of the most aggressive and lethal of human cancers, with a lack of prognostic and predictive biomarkers and effective therapeutic treatments contributing to its poor prognosis and high mortality rate. Perturbations in tyrosine kinase signalling are characteristic of many human cancers. A previous mass spectrometry-based phosphoproteomic screen identified, RON, a receptor tyrosine kinase; and SgK223, a pseudokinase that is characterised by substitutions in its kinase domain particularly in the DFG motif that is known to be conserved among active kinases and is critical for kinase catalytic activity, as possible molecular drivers and hence potential therapeutic targets and/or biomarkers for PC. Previous studies show that RON exhibits increased expression during PC progression and that increased RON promotes cell migration and invasion, and gemcitabine resistance in PC cells in pre-clinical experimental models. However prior to this study, the prognostic significance of RON expression in PC was unknown. In this study, RON expression was characterised in three independent cohorts totalling 492 PC patients, and the relationship between RON expression and overall survival with and without gemcitabine treatment were assessed. Collectively, these data showed that RON expression was not associated with survival or adjuvant gemcitabine therapeutic responsiveness in resected PC. However, this does not exclude RON as a potential therapeutic target. Unlike RON, SgK223 has never been directly implicated in PC prior to this study. For investigating SgK223, an overexpression cell line model was established in human pancreatic duct epithelial (HPDE) cells. SgK223 overexpression in HPDE cells resulted in an elongated cellular morphology, enhanced STAT3 tyrosine phosphorylation and transcriptional activity, and increased cell migration and invasion in transwell assays, which were able to be prevented through inhibiting STAT3. Upstream of STAT3, JAK1 phosphorylation also increased, and its inhibition prevented increased STAT3 phosphorylation in SgK223-overexpressing cells. Src, ERK, and AKT, pathways were also assessed, but were not activated by SgK223 overexpression. Collectively, these data identify a role for SgK223 in STAT3-mediated cell invasiveness in PC. Moreover, this study also identifies SgK223 as a potential therapeutic target and/or biomarker particularly for JAK1/STAT3-directed therapies against PC.