A somatic gain-of-function mutation in codon 12 of the KRAS gene is found in 35% of colorectal cancers. This mutation impairs which intrinsic enzymatic activity of the Ras protein, leading to constitutive activation of downstream MAPK signaling?

• A GTPase activity ✓
• B Tyrosine kinase activity
• C Adenylyl cyclase activity
• D Phospholipase C activity

Explanation

Ras is a GTPase that is normally self-inactivating: it hydrolyzes GTP→GDP. Codon 12/13 mutations abolish this intrinsic GTPase activity, locking Ras in the GTP-bound (active) state and constitutively activating the RAS-RAF-MEK-ERK (MAPK) cascade and PI3K-AKT pathway. This is clinically important because KRAS-mutant CRC does not respond to anti-EGFR antibodies like cetuximab.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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