title: Mitogen-activated protein/extracellular signal-regulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: University Hospital Zurich, Department of Dermatology, Zurich, Switzerland.
authors.forename: Karin
authors.initials: K
authors.lastname: Schad
authors.forename: Katrin
authors.initials: K
authors.lastname: Baumann Conzett
authors.forename: Marie C
authors.initials: MC
authors.lastname: Zipser
authors.forename: Valérie
authors.initials: V
authors.lastname: Enderlin
authors.forename: Jivko
authors.initials: J
authors.lastname: Kamarashev
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D000328:Adult; D017209:Apoptosis; D001562:Benzimidazoles / Q000009:adverse effects* / Q000627:therapeutic use; D003875:Drug Eruptions / Q000209:etiology; D005076:Exanthema / Q000139:chemically induced; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006706:Homeostasis; D006801:Humans; D015603:Keratinocytes / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010859:Pigmentation Disorders / Q000139:chemically induced*; D047428:Protein Kinase Inhibitors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases