Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibition Results in Biphasic Alteration of Epidermal Homeostasis with Keratinocytic Apoptosis and Pigmentation Disorders

Abstract

Purpose: Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway is constitutively activated in melanoma. AZD6244 blocks MEK1/2, inhibiting ERK phosphorylation. We focus on associated cutaneous toxicity and we attempt to understand the underlying pathophysiology and design treatment strategies.Experimental Design: Dermatologic conditions of 22 patients with unresectable melanoma stage III/ IV in a phase II trial were evaluated. Thirteen patients received AZD6244 initially, and nine patients were treated with AZD6244 following tumor progression with temozolomide. Biopsies were compared with matched controls in normal skin. Immunohistochemistry was performed. Half-side treatment of acute skin toxicity compared therapeutic options.Results: Nineteen of 22 (86%) AZD6244-treated patients presented with cutaneous eruptions. Seventeen patients (77%) developed acute papulopustular rash. Chronic skin changes included xerosis, paronychia, and fissured fingertips, resembling cutaneous toxicity of epidermal growth factor receptor inhibition. In addition, we observed reduced pigmentation of hair and skin. Histology of acute skin lesions revealed a significant increase of apoptotic keratinocytes (P = 0.0008), focal neutrophilic infiltrates, destruction of the adnexal structures by neutrophils, and reduced cytokeratins. A significant proliferation shift from basal to suprabasal keratinocytes was shown in acute and chronic lesions. The number and viability of melanocytes was not affected. Corticosteroids plus antibacterial topical therapy ameliorate acute skin toxicity.Conclusions: AZD6244-associated skin reactions partly overlap with those observed upon epidermal growth factor receptor inhibition. Additionally, pigmentation of skin and hair is affected. The interruption of the MEK signaling pathway results in an acute keratinocyte stress response with disturbed epidermal homeostasis, inflammation, and tissue damage. Chronic adaptation controls inflammatory tissue damage but leads to cutaneous malfunctions that explain chronic skin toxicity. Clin Cancer Res; 16(3); 1058-64. ©2010 AACR.Mutations and amplifications of oncogenes are frequent genetic alterations in cancer that result in the constitutive activation of pathways promoting proliferation and survival (1). For example, kinases involved in the RAS-RAFmitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) signaling pathway are thus activated in most melanomas (2, 3). Critically, this particular malignancy is increasing in incidence worldwide and the current lifetime risk is estimated to be 1:70 for European populations (4).Advanced melanoma palliative therapy using cytostatic drugs, either alone or in combinatory settings, has yielded disappointing results (5). For patients with distant metastases, treatment with dacarbazine remains the standard chemotherapy despite a response rate of under 10% (6). Patients with advanced melanoma are therefore often treated in controlled clinical trial...

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