RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• BRAF inhibitors like vemurafenib are associated with cutaneous squamous-cell carcinomas and keratoacanthomas.
• Understanding the molecular drivers of these lesions is crucial for patient management.

Purpose of the Study:

• To investigate oncogenic mutations in skin lesions from patients treated with vemurafenib.
• To elucidate the molecular mechanisms underlying vemurafenib-induced skin tumors.

Main Methods:

• Molecular analysis of tumor samples for mutations in HRAS, KRAS, NRAS, CDKN2A, and TP53.
• Functional studies using BRAF inhibitors and RAS-mutant cell lines.
• In vivo studies using a mouse model of skin carcinogenesis.

Main Results:

• RAS mutations, predominantly HRAS Q61L, were identified in 60% of the analyzed lesions.
• Vemurafenib treatment led to increased proliferation of HRAS Q61L-mutant cells via MAPK/ERK signaling.
• In a mouse model, vemurafenib analogue PLX4720 accelerated HRAS-mutant lesion growth, which was inhibited by a MEK inhibitor.

Conclusions:

• RAS mutations, particularly HRAS, are frequent in vemurafenib-associated skin cancers.
• Paradoxical MAPK pathway activation drives accelerated lesion growth.
• Targeting MEK offers a potential therapeutic strategy to counteract this effect.