KRAS G12C / G12S

Class

KRAS inhibitor (oral small molecule)

Pathway

RAS-MAPK signaling blockade in KRAS G12C/G12S-mutant tumors

KRAS is a small GTPase that acts as a molecular switch within the RAS-MAPK signaling pathway, cycling between an active, GTP-bound state and an inactive, GDP-bound state to control cell growth and division signals. Certain point mutations at codon 12, including G12C and G12S, impair the protein's ability to return to its inactive state, leaving downstream growth signaling persistently engaged and driving uncontrolled proliferation in a range of solid tumors. Small-molecule inhibitors directed at these specific mutant forms are designed to trap KRAS in its inactive conformation, interrupting the signal before it reaches downstream effectors such as RAF, MEK, and ERK. Because different G12 substitutions create subtly different pocket shapes on the mutant protein, most inhibitors developed to date have been selective for a single variant, most commonly G12C. An agent capable of engaging both G12C and G12S addresses a broader population of tumors bearing structurally related codon-12 mutations without requiring separate drugs for each, which is relevant to cancers such as non-small cell lung cancer, colorectal cancer, and pancreatic cancer where these mutations occur.