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Summary
The control of normal cellular homeostasis is a function of signaling by the RAS guanosine triphosphatases (GTPases) KRAS, NRAS, and HRAS and their downstream signaling proteins, such as the RAF kinases (BRAF and CRAF), mitogen-activated protein kinase (MAPK) kinase (MEK), and extracellular signal–regulated kinase (ERK), which together constitute the RAS-MAPK pathway (1). This pathway is dysregulated in human diseases, particularly cancer, in which mutations or other nongenetic events hyperactivate the pathway in more than 50% of cases (1). Activating mutations in RAS genes occur in more than 30% of all cancers and seemingly lock RAS into a constitutively active, GTP-bound state to signal autonomously without the need for upstream input (1). Therapeutic suppression of pathogenic RASMAPK signaling to maximize disease control in cancer patients remains an elusive goal. Multiple strategies targeting upstream [e.g., receptor tyrosine kinases (RTKs)] or downstream (e.g., MEK) RAS pathway proteins to limit RAS-GTP–mediated signaling in RAS-MAPK pathway–driven cancers are under evaluation (1–3). However, recent studies have extended our knowledge of how certain forms of oncogenic RAS and other oncogenic MAPK pathway proteins function not in an autonomous manner but instead semiautonomously, such that they still respond to upstream regulation (4–8). These findings reveal mechanisms by which RAS signaling is dysregulated in cancer and highlight newly identified therapeutic strategies with the potential to target oncogenic RAS-MAPK signaling.
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