Epidermal growth factor receptor signalling in keratinocyte biology: implications for skin toxicity of tyrosine kinase inhibitors.
The epidermal growth factor receptor (EGFR) and its ligands have been long recognized as centrally involved in the growth and repair process of epithelia, as well as in carcinogenesis. In addition, the EGFR has been demonstrated to be importantly involved in the control of inflammatory responses. During this last decade, a number of highly specific agents targeting this system have become an integral component of pharmacologic strategies against many solid malignancies. These drugs have led to increased patient survival and made therapy more tolerant when compared to conventional cytotoxic drugs. Nonetheless, their use is associated with a constellation of toxic effects on the skin, including follicular pustules, persistent inflammation, xerosis and pruritus, and enhanced susceptibility to infections. This dramatic impairment of skin homoeostasis underscores the centrality of the EGFR-ligand system in the whole skin immune system. So far, no mechanism-based approaches are available to specifically counteract the adverse effects of anti-EGFR drugs or any other class of tyrosine kinase inhibitors. Only the knowledge of the cellular and molecular events underlying these adverse effects in humans, combined with in vitro/in vivo models able to mimic these toxic responses, may guide the development of mechanism-based treatment or prevention strategies.
Laboratory of Experimental Immunology, IDI-IRCCS, Rome, Italy, s.pastore@idi.it.
Saveria
S
Pastore
Daniela
D
Lulli
Giampiero
G
Girolomoni
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D003875:Drug Eruptions / Q000209:etiology / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008024:Ligands; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000187:drug effects* / Q000473:pathology
D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors