Not all RAS mutations are equal: A detailed review of the functional diversity of RAS hot spot mutations.

The RAS family of small GTPases are among the most frequently mutated oncogenes in human cancer. Approximately 20% of cancers harbor a RAS mutation, and >150 different missense mutations have been detected. Many of these mutations have mutant-specific biochemical defects that alter nucleotide binding and hydrolysis, effector interactions and cell signaling, prompting renewed efforts in the development of anti-RAS therapies, including the mutation-specific strategies. Previously viewed as undruggable, the recent FDA approval of a KRAS^G12C-selective inhibitor has offered real promise to the development of allele-specific RAS therapies. A broader understanding of the mutational consequences on RAS function must be developed to exploit additional allele-specific vulnerabilities. Approximately 94% of RAS mutations occur at one of three mutational "hot spots" at Gly¹², Gly¹³ and Gln⁶¹. Further, the single-nucleotide substitutions represent >99% of these mutations. Within this scope, we discuss the mutational frequencies of RAS isoforms in cancer, mutant-specific effector interactions and biochemical properties. By limiting our analysis to this mutational subset, we simplify the analysis while only excluding a small percentage of total mutations. Combined, these data suggest that the presence or absence of select RAS mutations in human cancers can be linked to their biochemical properties. Continuing to examine the biochemical differences in each RAS-mutant protein will continue to provide additional breakthroughs in allele-specific therapeutic strategies.