Targeting RAS for Cancer Treatment: What a Long, Strange Trip It's Been

The 1982 discovery of mutationally activated RAS genes in human cancers launched a decades-long search for anti-RAS therapies for cancer treatment. Despite the repeated emergence of new knowledge that initiated fresh directions for drug discovery, strategy after strategy culminated in disappointment. At last, the 2013 discovery of a druggable pocket in RAS renewed efforts to directly target RAS and led, only 8 short years later, to the first clinically effective anti-RAS drug. Approved to treat one KRAS mutant (glycine-12-cysteine) in one cancer (non-small-cell lung cancer), this first step created new hope that the RAS-driven cancer dragon could be slayed. Here, we revisit past efforts to drug RAS and discuss important lessons learned from each misstep and unexpected finding, provide a snapshot of the current state of the art in RAS drug discovery, and describe important challenges ahead as the field seeks to build on recent successes and advance more clinically effective therapies.