Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics
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Jeffery Chakedis1, Randall French1, Michele Babicky1, Dawn Jaquish1, Evangeline Mose1, Peter Cheng1, Patrick Holman1, Haleigh Howard1, Jaclyn Miyamoto1, Paula Porras1, Zakk Walterscheid1, Carsten Schultz-Fademrecht2, Christina Esdar3, Oliver Schadt3, Jan Eickhoff2, Andrew M. Lowy1
1Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
2Lead Discovery Center GmbH, Dortmund, Germany
3Merck KGaA, Darmstadt, Germany
Andrew M. Lowy, email: email@example.com
Keywords: RON, pancreatic cancer, isoform, alternative splicing, tyrosine kinase inhibitor
Received: March 03, 2016 Accepted: May 23, 2016 Published: June 14, 2016
The RON tyrosine kinase receptor is under investigation as a novel target in pancreatic cancer. While RON mutations are uncommon, RON isoforms are produced in cancer cells via a variety of mechanisms. In this study we sought to: 1) characterize RON isoform expression in pancreatic cancer, 2) investigate mechanisms that regulate isoform expression, and 3) determine how various isoforms effect gene expression, oncogenic phenotypes and responses to RON directed therapies. We quantified RON transcripts in human pancreatic cancer and found expression levels 2500 fold that of normal pancreas with RON isoform expression comprising nearly 50% of total transcript. RNA seq studies revealed that the short form (sfRON) and P5P6 isoforms which have ligand independent activity, induce markedly different patterns of gene expression than wild type RON. We found that transcription of RON isoforms is regulated by promoter hypermethylation as the DNA demethylating agent 5-aza-2’-deoxycytidine decreased all RON transcripts in a subset of pancreatic cancer cell lines. The viability of sfRON-expressing HPDE cells was reduced by a RON specific small molecule inhibitor, while a therapeutic monoclonal antibody had no demonstrable effects. In summary, RON isoforms may comprise half of total RON transcript in human pancreatic cancer and their expression is regulated at least in part by promoter hypermethylation. RON isoforms activate distinct patterns of gene expression, have transforming activity and differential responses to RON directed therapies. These findings further our understanding of RON biology in pancreatic cancer and have implications for therapeutic strategies to target RON activity.
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