1. Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer.
- Author
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Germino EA, Miller JP, Diehl L, Swanson CJ, Durinck S, Modrusan Z, Miner JH, and Shaw AS
- Subjects
- Adenocarcinoma complications, Adenocarcinoma genetics, Adenocarcinoma metabolism, Adenocarcinoma pathology, Animals, Carcinogenesis genetics, Disease Models, Animal, Mice, Mice, Inbred C57BL, Morbidity, Pancreatic Neoplasms complications, Pancreatic Neoplasms metabolism, Rectal Prolapse complications, Rectal Prolapse prevention & control, Tumor Suppressor Protein p53 metabolism, Gene Deletion, Homozygote, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Protein Kinases deficiency, Protein Kinases genetics, ras Proteins metabolism
- 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.
- Published
- 2018
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