Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer

PLoS One. 2018 Mar 29;13(3):e0194998. doi: 10.1371/journal.pone.0194998. eCollection 2018.

Abstract

Given the frequency with which MAP kinase signaling is dysregulated in cancer, much effort has been focused on inhibiting RAS signaling for therapeutic benefit. KSR1, a pseudokinase that interacts with RAF, is a potential target; it was originally cloned in screens for suppressors of constitutively active RAS, and its deletion prevents RAS-mediated transformation of mouse embryonic fibroblasts. In this work, we used a genetically engineered mouse model of pancreatic cancer to assess whether KSR1 deletion would influence tumor development in the setting of oncogenic RAS. We found that Ksr1-/- mice on this background had a modest but significant improvement in all-cause morbidity compared to Ksr1+/+ and Ksr1+/- cohorts. Ksr1-/- mice, however, still developed tumors, and precursor pancreatic intraepithelial neoplastic (PanIN) lesions were detected within a similar timeframe compared to Ksr1+/+ mice. No significant differences in pERK expression or in proliferation were noted. RNA sequencing also did not reveal any unique genetic signature in Ksr1-/- tumors. Further studies will be needed to determine whether and in what settings KSR inhibition may be clinically useful.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / complications
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Carcinogenesis / genetics
  • Disease Models, Animal
  • Gene Deletion*
  • Homozygote*
  • Mice
  • Mice, Inbred C57BL
  • Morbidity
  • Pancreatic Neoplasms / complications
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Protein Kinases / deficiency*
  • Protein Kinases / genetics*
  • Rectal Prolapse / complications
  • Rectal Prolapse / prevention & control
  • Tumor Suppressor Protein p53 / metabolism
  • ras Proteins / metabolism*

Substances

  • Tumor Suppressor Protein p53
  • Protein Kinases
  • KSR-1 protein kinase
  • ras Proteins