Localized RAS signaling drives cancer

Dysregulated signaling through the core RAS pathway (RAS-RAF-MEK-ERK) provides the oncogenic drive for many cancers. Activating mutations in RAS GTPases or RAF kinases occur in approximately 40% of human malignancies, and many others contain mutant or overexpressed receptor tyrosine kinases (RTKs) that induce aberrant signaling through the RAS pathway. RAS cancers are particularly aggressive and are refractory to current therapeutic interventions (mainly RAF and MEK inhibitors), typically due to narrow therapeutic windows, paradoxical pathway activation, feedback induction of PI3 kinase/Akt signaling, and/or drug resistance [1]. Moreover, RAS proteins are not particularly amenable to direct inhibition by small molecules. Therefore, to identify new therapeutic targets for RAS cancers it is imperative to further elucidate the biochemistry and cell biology of RAS effector pathways, with the goal of identifying actionable differences between normal and oncogenic RAS signaling