Mitogen-activated protein/extracellular signal-regulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Karin SchadReinhard Dummer

Abstract

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. 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. 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...Continue Reading

Citations

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