NCI-H358-KRAS-G12C-H95C-KI Cell Line

KRAS-G12C-H95C represents a novel double mutation in the KRAS oncogene, combining the well-studied G12C mutation with the rare H95C variant. The G12C mutation, frequently observed in non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic cancer, locks KRAS in an active GTP-bound state by impairing GTPase activity, driving uncontrolled cell proliferation and survival. The H95C mutation, located in the α3-helix of KRAS, is less characterized but may influence protein conformation and interactions with regulators such as GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins). Preliminary structural analyses suggest that H95C could alter the stability of KRAS or its binding affinity to downstream effectors, potentially modulating signaling pathways like MAPK/ERK and PI3K/AKT. The co-occurrence of G12C and H95C raises questions about their combined effects on KRAS function, drug binding, and therapeutic response, particularly to G12C-specific inhibitors such as sotorasib and adagrasib. Investigating this double mutation could provide insights into resistance mechanisms and inform the design of next-generation KRAS inhibitors. Further studies are needed to elucidate the biochemical and clinical implications of KRAS-G12C-H95C, including its role in tumorigenesis and potential as a therapeutic target.