Oncotarget

Research Papers:

Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics

Jeffery Chakedis, Randall French, Michele Babicky, Dawn Jaquish, Evangeline Mose, Peter Cheng, Patrick Holman, Haleigh Howard, Jaclyn Miyamoto, Paula Porras, Zakk Walterscheid, Carsten Schultz-Fademrecht, Christina Esdar, Oliver Schadt, Jan Eickhoff and Andrew M. Lowy _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:45959-45975. https://doi.org/10.18632/oncotarget.10009

Metrics: PDF 1471 views  |   HTML 1939 views  |   ?  


Abstract

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

Correspondence to:

Andrew M. Lowy, email: alowy@ucsd.edu

Keywords: RON, pancreatic cancer, isoform, alternative splicing, tyrosine kinase inhibitor

Received: March 03, 2016    Accepted: May 23, 2016    Published: June 14, 2016

ABSTRACT

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 10009