[gdpawel]

Skin tumors induced by sorafenib; Paradoxical RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53 and TGFBR1

Jean-Philippe Arnault (1), Christine Mateus (2), Bernard Escudier (3), Gorana Tomasic (4), Janine Wechsler (1), Emilie Hollville (1), Jean-Charles Soria (5), David Malka (6), Alain Sarasin (7), Magalie Larcher (8), Jocelyne Andree (9), Nyam Kamsu-Kom (10), Lise Boussemart (1), Ludovic Lacroix (11), Alain Spatz (12), Alexander M Eggermont (13), Sabine Druilenec (14), Stephan Vagner (15), Alain Eychene (14), Nicolas Dumaz (16), and Caroline Robert (2)

1. Dermatology, Institut Gustave Roussy

2. Inserm U981, Institut Gustave Roussy
3. Unite d Immunotherapie, Institut Gustave Roussy
4. Pathology, Institut Gustave Roussy
5. medicine, Institute Gustave Roussy
6. Medicine, Institut Gustave Roussy
7. CNRS, Institut Gustave Roussy
8. INSERM U 1021, Institut Curie
9. INSERM U976, Hopital St Louis
10. INSERM U981, Institut Gustave Roussy
11. Translational Research Laboratory, Institute Gustave Roussy
12. Department of Pathology, Jewish General Hospital & McGIll University
13. Director general, Institut de cancerologie Gustave Roussy
14. Institut Curie - CNRS UMR 146, Institut Curie
15. INSERM U 981, Institut Gustave Roussy
16. Hopital Saint Louis, INSERM U976

Abstract

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.

Source: Clinical Cancer Research, American Association for Cancer Research

http://clincancerres.aacrjournals.or...-1344.abstract