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Paradoxical MAPK Activation — SCE Medical Oncology MCQ

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HardImmunotherapy & Targeted TherapyParadoxical MAPK ActivationSCE Medical Oncology

A patient receiving vemurafenib monotherapy develops multiple keratoacanthomas and cutaneous squamous-cell carcinomas. Which molecular event most directly explains this toxicity in non-melanoma keratinocyte clones?

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Correct answer: B — Drug-induced RAF-dimer transactivation with ERK signalling in RAS-activated, BRAF-wild-type cells

Selective BRAF inhibition can transactivate RAF dimers when upstream RAS is active in BRAF-wild-type keratinocytes, increasing MEK-ERK signalling and selecting keratoacanthoma or squamous-cell-carcinoma clones. Vemurafenib does not directly disable nucleotide-excision repair. It is not an EGFR inhibitor. It does not cause the toxicity through systemic T-cell depletion and HPV expansion. Direct telomerase activation is not the established mechanism.

Reference: RAF inhibition and induction of cutaneous squamous-cell carcinoma (Published February 2011): https://pubmed.ncbi.nlm.nih.gov/21192261/; NICE NG14 melanoma: recommendations (Updated July 2022; minor amendment January 2024): https://www.nice.org.uk/guidance/ng14/chapter/recommendations