KRAS G12C Mutation

• Sotorasib Is Not Effective in a KRAS-Mutated Patient With Brain Metastases From Lung Adenocarcinoma due to Multiple Gene Co-Mutations
• Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A
• Intracranial Activity of Sotorasib in KRAS(G12C)-Mutated Recurrent Glioblastoma
• A real-world pharmacovigilance study of KRAS G12C mutation inhibitors based on the food and drug administration adverse event reporting system
• Antigen presentation deficiency, mesenchymal differentiation, and resistance to immunotherapy in the murine syngeneic CT2A tumor model
• Computational study of novel natural inhibitors targeting Kirsten rat sarcoma viral oncogene homolog G12C
• A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers
• Novel natural inhibitors targeting KRAS G12C by computational study

The KRAS G12C mutation is a specific alteration in the KRAS gene that results in uncontrolled cell growth and cancer development. It is now a target for precision therapies.

KRAS is part of the RAS family of oncogenes and encodes a small GTPase involved in:

• Cell proliferation
• Cell differentiation
• Cell survival

It cycles between active (GTP-bound) and inactive (GDP-bound) states. Mutations lock it in the active state.

• Mutation: Glycine (G) → Cysteine (C) at codon 12
• Mechanism: Point mutation (GGT → TGT)
• Effect: Constitutive activation of KRAS protein

[folded|Click to expand: Cancer types with KRAS G12C]

• Non-Small Cell Lung Cancer (NSCLC): ~13%
• Colorectal Cancer: ~3–4%
• Pancreatic Cancer: <1%
• Other: rare cases (endometrial, ovarian, etc.)

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KRAS G12C is targetable with covalent inhibitors:

• Adagrasib (Krazati)
• Sotorasib (Lumakras)

These drugs bind KRAS G12C in its inactive (GDP-bound) form, blocking downstream signaling.

Mechanisms of resistance:

• Secondary KRAS mutations
• Reactivation via bypass pathways (e.g., EGFR, MET)

Current strategies:

• KRAS inhibitors + checkpoint inhibitors (PD-1/PD-L1)
• KRAS inhibitors + EGFR inhibitors (e.g., cetuximab)
• KRAS inhibitors + SHP2/MEK inhibitors