A patient with metastatic colorectal cancer is found to have a KRAS wild-type tumour and is given cetuximab (anti-EGFR monoclonal antibody). Why is KRAS wild-type status necessary for cetuximab to be effective?
- A Mutant KRAS is constitutively active downstream of EGFR, so EGFR blockade cannot suppress RAS/MAPK signalling ✓
- B Mutant KRAS overexpresses EGFR on the cell surface, preventing cetuximab binding
- C KRAS mutation prevents cetuximab internalisation via clathrin-coated pits
- D Wild-type KRAS is required for antibody-dependent cell-mediated cytotoxicity (ADCC)
Correct answer: A. Mutant KRAS is constitutively active downstream of EGFR, so EGFR blockade cannot suppress RAS/MAPK signalling
Explanation
KRAS is a GTPase that lies immediately downstream of EGFR in the RAS/MAPK proliferation pathway. In tumours with activating KRAS mutations (codons 12/13), KRAS is constitutively active regardless of upstream EGFR signalling — meaning that blocking EGFR with cetuximab cannot suppress the downstream oncogenic pathway. Only in KRAS wild-type tumours can EGFR inhibition effectively halt the RAS/MAPK cascade. Therefore, all patients considered for anti-EGFR therapy (cetuximab, panitumumab) in mCRC must have tumours tested for RAS mutations first.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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