Skin tumors induced by sorafenib; Paradoxical RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53 and TGFBR1
Menée in vitro et in vivo à partir de 31 échantillons de lésions cutanées prélevés sur des patients recevant un traitement au sorafenib, cette étude analyse les caractéristiques cliniques, pathologiques et moléculaires de ces lésions afin d'identifier des facteurs associés à leur évolution d'une forme bénigne en tumeur maligne
Purpose:The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We performed a clinical, pathological and molecular study of skin lesions occurring in patients receiving sorafenib. Experimental Design:31 skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hotspots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1 and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes. Results:We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1 and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV-signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency towards increased MAPK pathway activation in normal skin. Sorafenib induced BRAF-CRAF dimerization in cultured keratinocytes and activated CRAF with a dose-dependent effect on MAP-kinase pathway activation and on keratinocyte proliferation. Conclusions:Sorafenib induces keratinocyte proliferation in vivo and a time and dose-dependent activation of the MAP-kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors.