In pancreatic ductal adenocarcinoma (PDAC), the dominant oncogenic driver is a KRAS mutation. The KRAS protein locked in GTP-bound active state continuously activates which downstream oncogenic pathway?

• A JAK-STAT3 pathway exclusively
• B PI3K-AKT-mTOR and RAF-MEK-ERK pathways concurrently ✓
• C Hedgehog (SHH) pathway through KRAS-SMO interaction
• D Wnt-beta-catenin pathway through KRAS-APC disruption

Explanation

KRAS mutations (predominantly G12D and G12V) in PDAC lock KRAS in the GTP-bound active state by preventing intrinsic GTPase activity. Active KRAS simultaneously activates multiple effector arms: the RAF-MEK-ERK (MAPK) pathway promoting proliferation and survival, and the PI3K-AKT-mTOR pathway promoting growth and resistance to apoptosis. These parallel oncogenic signals explain the difficulty of KRAS-targeted therapies requiring combination approaches. JAK-STAT3 is driven by cytokine receptors, not directly by KRAS. SHH pathway is upregulated in PDAC stroma but not directly via KRAS-SMO interaction.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.