Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management

J Eur Acad Dermatol Venereol. 2013 Jan;27(1):11-8. doi: 10.1111/j.1468-3083.2012.04546.x. Epub 2012 Apr 28.


Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late-stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS-RAF-MEK-ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Drug Eruptions / etiology*
  • Drug Eruptions / physiopathology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Genes, ras / drug effects
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics
  • Male
  • Molecular Targeted Therapy / adverse effects
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Prognosis
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / therapeutic use
  • Risk Assessment
  • Signal Transduction
  • Treatment Outcome
  • raf Kinases / antagonists & inhibitors
  • raf Kinases / genetics
  • raf Kinases / metabolism


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases