title: Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients.
abstract: OBJECTIVE
  Epidermal growth factor receptor inhibitor (EGFRI) induced skin toxicity has a prognostic value suggesting skin toxicity can be a useful surrogate marker for successful epidermal growth factor receptor (EGFR) inhibition, improved response and survival. But the pathophysiology of EGFRI induced skin toxicity remains elusive. However the involvement of immunological mechanisms has been speculated. This study investigates the possible underlying mechanism of EGFR inhibition associated cytokine production in keratinocytes as well as in patients after treatment with epidermal growth factor receptor inhibitors (EGFRIs).
  
  
  METHODS
  Normal human epidermal keratinocytes (NHEK) were incubated for 2 and 24h with different concentrations of EGFRI (erlotinib) for Western blot analysis and cytokine expression analysis, respectively. Inhibition of EGFR, extracellular-signal-regulated kinase 1/2 (Erk 1/2) and c-Jun was examined by Western blot analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the NHEK cell supernatant and also in the serum of 186 cancer patients who are followed up for EGFRI induced skin rash.
  
  
  RESULTS
  A significant inhibitory effect of EGFRI was seen on EGFR (Y845), Erk 1/2 and c-Jun in a dose dependent manner. Further downstream, increased CC-chemokine ligand 2 (CCL2), CC-chemokine ligand 5 (CCL5) and decreased interleukin-8 (IL-8) or CXCL8 expression was observed in keratinocytes. In EGFRI treated patients, low levels of serum CXCL8 corresponding to stronger EGFR inhibition were associated with a higher grade of skin toxicity (p=0.0016) and a prolonged overall survival (p=0.018).
  
  
  CONCLUSIONS
  The results obtained in this study indicate that EGFRI can regulate cytokines by modulating EGFR signalling pathway in keratinocytes. Moreover, serum levels of CXCL8 in EGFRI treated patients may be important for individual EGFRI induced skin toxicity and patient's survival.
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany.
authors.forename: Tanusree
authors.initials: T
authors.lastname: Paul
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schumann
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rüdiger
authors.affiliation: Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boeck
authors.affiliation: Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Kächele
authors.affiliation: Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.affiliation: Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: Vivien
authors.initials: V
authors.lastname: Hichert
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.affiliation: Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany; Faculty of Medicine, University of Bonn, Bonn, Germany. Electronic address: Julia.Stingl@bfarm.de.
authors.forename: Julia Carolin
authors.initials: JC
authors.lastname: Stingl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D012871:Skin Diseases / Q000139:chemically induced* / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D016207:Cytokines; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: CXCL8/IL-8; EGFR; EGFRI; Erk 1/2; Keratinocytes; Skin toxicity