Abstract
RAS proteins (HRAS, KRAS, NRAS) contribute to many physiological signal transduction pathways involving cell growth, cell division, and survival. RAS proteins possess GTPase activity. These proteins toggle between inactive and active forms; the conversion of inactive RAS-GDP to active RAS-GTP is facilitated by guanine nucleotide exchange factors (GEFs) turning the switch on and the intrinsic RAS-GTPase activity accelerated by the GTPase activating proteins (GAPs) turning the switch off. RAS is the upstream component of the RAS-RAF-MEK-ERK and the PI3-kinase-AKT signaling cascades. One-fifth of all cancers bear RAS mutations and about 75% of them involve KRAS. Except for the GTP/GDP binding site, RAS proteins lack deep surface pockets able to bind high-affinity inhibitors, which impeded the development of specific antagonists. KRAS mutations occur frequently in pancreatic, lung, and colorectal cancers, which are among the deadliest cancers worldwide. RAS mutations include those of codon 12 G12D/V/C/R, codon 13 G13D, and codon 61 Q61R/K/L. Studies conducted over the last 15 years led to the discovery of the so-called RAS switch II pocket. Sotorasib and adagrasib, which interact with this pocket and directly block the action of KRAS following the covalent modification of KRAS C12, are FDA-approved for the second-line treatment of KRASG12C-mutant non-small cell lung cancer. Daraxonrasib, which is an indirect inhibitor of wildtype and mutant H/K/NRAS isoforms, is FDA approved for the second-line treatment of all RAS-mutant pancreatic cancers. Daraxonrasib first forms a complex with cyclophilin A (a chaperone protein), which then interacts with active RAS to block RAS signaling.