Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS

Abstract

RAS proteins (HRAS, KRAS, NRAS) participate in many physiological signal transduction processes related to cell growth, division, and survival. The RAS proteins are small (188/189 amino acid residues) and they function as GTPases. These proteins toggle between inactive and functional forms; the conversion of inactive RAS-GDP to active RAS-GTP as mediated by guanine nucleotide exchange factors (GEFs) turns the switch on and the intrinsic RAS-GTPase activity stimulated by the GTPase activating proteins (GAPs) turns the switch off. RAS is upstream to the RAS-RAF-MEK-ERK and the PI3-kinase-AKT signaling modules. Importantly, the overall incidence of RAS mutations in all cancers is about 19% and RAS mutants have been a pharmacological target for more than three decades. About 84% of all RAS mutations involve KRAS. Except for the GTP/GDP binding site, the RAS proteins lack other deep surface pockets thereby hindering efforts to identify high-affinity antagonists; thus, they have been considered to be undruggable. KRAS mutations frequently occur in lung, colorectal, and pancreatic cancers, the three most deadly cancers in the United States. Studies within the last decade demonstrated that the covalent modification of KRAS C12, which accounts for about 10% of all RAS mutations, led to the discovery of an adjacent pocket (called the switch II pocket) that accommodated a portion of the drug. This led to the development of sotorasib as a second-line treatment of KRAS^G12C-mutant non-small cell lung cancer. Considerable effort also has been expended to develop MAP kinase and PI3-kinase pathway inhibitors as indirect RAS antagonists.

Keywords: Adagrasib (PubChem CID: 138611145); Belvarafenib (PubChem CID: 89655386); Buparlisib (PubChem CID: 16654980); Cancer mutations; Lifirafenib (PubChem CID: 89670174); MAP kinase signaling pathway; Naporafenib (PubChem CID: 90456533); Non-small cell lung cancer; PI3-kinase signaling pathway; Pancreatic cancer; Pictilisib (PubChem CID: 17755052); RO5126766 (PubChem CID: 16719221); Sotorasib (PubChem CID: 137278711); Targeted covalent inhibitors; Tipifarnib (PubChem CID: 159324); Ulixertinib (PubChem CID: 11719003).