Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1

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 carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.Experimental Design: Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots 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 toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin.Sorafenib induced BRAF-CRAF dimerization in cultured keratinocytes and activated CRAF with a dosedependent effect on MAP-kinase pathway activation and on keratinocyte proliferation.Conclusion: 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.

Inflammation and Hras signaling control epithelial–mesenchymal transition during skin tumor progression

“…Squamous carcinomas of the skin, head and neck, and lung have a strong link to carcinogen exposure, exhibit similar morphological and molecular features, and rank among the largest causes of death from cancer worldwide (Stransky et al 2011;Wang et al 2011;Hammerman et al 2012). Tumors of these types have a significant frequency of Hras mutations, including the same codon 61 mutation that is induced by DMBA in mouse skin (Arnault et al 2012;Oberholzer et al 2012;Su et al 2012). Deletion and/or mutation of Cdkn2a has also been specifically linked to poor survival of human skin cancer patients (Kusters-Vandevelde et al 2010).…”

Vemurafenib Cooperates with HPV to Promote Initiation of Cutaneous Tumors

“…Most notably 18% to 60% of the clinical biopsies harbor a RAS mutation (11)(12)(13), and treatment with a vemurafenib analogue (PLX-4720) also decreased tumor latency in a mouse model for Hras-driven cSCC (13). However, 40% to 82% of keratoacanthomas and cSCCs from RAF inhibitor-treated patients are RAS wild-type, suggesting that accelerated oncogenesis of RAS-mutated cells is not the only mechanism involved.…”

Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

“…These tumor harbor Ras mutations with variably increased frequency (from 17% to 60% in different studies; refs. [8][9][10]. In addition, inhibitor treatment accelerates tumor development in a mouse model of chemical skin carcinogenesis (8), which partially depends on H-Ras and involves a strong inflammatory response (11).…”