The RAS oncogenes (HRAS, NRAS, and KRAS) compose the most frequently mutated class of oncogenes in human cancers (33%), prompting the search for anti-RAS inhibitors for cancer treatment. However, despite intensive effort, to date no effective anti-RAS strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic RAS for cancer treatment. Although HRAS was historically the most studied RAS gene, ironically, it is the isoform least mutated in human cancers. Mutations in KRAS are associated with the highest percentage of all human cancers (21.6%), followed by NRAS (8.0%), with HRAS mutations being the least frequently mutated (3.3%) (www.sanger.ac.uk/genetics/CGP/cosmic/). Prior to the exon sequencing of pancreatic cancer (PDAC), the most frequently mutated genes known to be associated with the progression of this cancer were KRAS and the TP53, CDKN2A, and SMAD4 tumor suppressors.
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