====== KRAS G12C Mutation ======

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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.

===== 🔬 What is KRAS? =====

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.

===== 🧬 The G12C Mutation =====

  * 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.)
[/folded]

===== 💊 Targeted Therapies =====

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.

===== 🔄 Resistance & Combinations =====

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