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RASopathic skin eruptions during vemurafenib therapy.

ABSTRACT: Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n?=?16), maculopapular exanthema (n?=?14), pruritus (n?=?8), folliculitis (n?=?5), burning feet (n?=?3), hair thinning (mild alopecia) (n?=?8), curly hair (n?=?2) and nail changes (n?=?2). Keratosis pilaris and acanthopapilloma were common skin reactions (n?=?12/n?=?13), as well as plantar hyperkeratosis (n?=?4), keratoacanthoma (n?=?5) and invasive squamous cell carcinoma (n?=?4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.

SUBMITTER: Rinderknecht JD

PROVIDER: S-EPMC3597638 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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RASopathic skin eruptions during vemurafenib therapy.

Rinderknecht Jeannine D JD Goldinger Simone M SM Rozati Sima S Kamarashev Jivko J Kerl Katrin K French Lars E LE Dummer Reinhard R Belloni Benedetta B

PloS one 20130314 3

<h4>Purpose</h4>Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.<h4>Patients and methods</h4>Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were c ...[more]

PMID: 23516541

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Project description:The BRAF inhibitor vemurafenib, approved for treating patients with BRAF V600E-mutant and unresectable or metastatic melanomas, rapidly induces cutaneous adverse events, including hyperkeratotic skin lesions and cutaneous squamous cell carcinomas (cSCC). To determine, how vemurafenib would provoke these adverse events, we utilized long-term in vitro skin equivalents (SEs) comprising epidermal keratinocytes and dermal fibroblasts in their physiological environment. We inserted keratinocytes with different genetic background [normal keratinocytes: NHEK, HaCaT (p53/mut), and HrasA5 (p53/mut+Hras/mut)] to analyze effects depending on the stage of carcinogenesis. We now show that vemurafenib activates MEK-ERK signaling in both, keratinocytes, and fibroblasts in vitro and in the in vivo-like SEs. As a consequence, vemurafenib does not provide a growth advantage but leads to a differentiation phenotype, causing accelerated differentiation and hyperkeratosis in the NHEK and normalized stratification and cornification in the transformed keratinocytes. Although all keratinocytes responded very similarly to vemurafenib in their expression profile, particularly with a significant induction of MMP1 and MMP3, only the HrasA5 cells revealed a vemurafenib-dependent pathophysiological shift to tumor progression, i.e., the initiation of invasive growth. This was shown by increased proteolytic activity allowing for penetration of the basement membrane and invasion into the disrupted underlying matrix. Blocking MMP activity, by the addition of ilomastat, prevented invasion with all corresponding degradative activities, thus substantiating that the RAS-RAF-MEK-ERK/MMP axis is the most important molecular basis for the rapid switch towards tumorigenic conversion of the HrasA5 keratinocytes upon vemurafenib treatment. Finally, cotreatment with vemurafenib and the MEK inhibitor cobimetinib prevented MEK-ERK hyperactivation and with that abolished both, the epidermal differentiation and the tumor invasion phenotype. This suggests that both cutaneous adverse events are under direct control of vemurafenib-dependent MEK-ERK hyperactivation and confirms the dependence on preexisting genetic alterations of the skin keratinocytes that determine the basis towards induction of tumorigenic progression.

Dataset Information

RASopathic skin eruptions during vemurafenib therapy.

Publications

RASopathic skin eruptions during vemurafenib therapy.

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