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

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.