Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients |
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| Affiliation: | 1. Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany;2. Department of Internal Medicine II, University of Ulm, Ulm, Germany;3. Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany;4. Department of Internal Medicine I, University of Ulm, Ulm, Germany;5. Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany;6. Faculty of Medicine, University of Bonn, Bonn, Germany;1. Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany;2. Department of Internal Medicine II, University of Ulm, Ulm, Germany;3. Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany;4. Department of Internal Medicine I, University of Ulm, Ulm, Germany;5. Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany;6. Faculty of Medicine, University of Bonn, Bonn, Germany;1. Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy;2. Academic Medical Center, University of Amsterdam, Department of Medical Psychology, Amsterdam, The Netherlands;3. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA;4. Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria;5. Division of Psychosocial Research & Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;6. Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK;7. Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK;8. Centre for Surgical Research, University of Bristol and University Hospitals NHS Foundation Trust, Bristol, UK;1. Department of Pathology, Ludwig-Maximilians-University of Munich, Germany;2. Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany;3. German Cancer Consortium (DKTK), Heidelberg, Germany;4. German Cancer Research Center (DKFZ), Heidelberg, Germany;5. Clovis Oncology Inc., San Francisco, CA, USA;6. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Germany;7. Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany;1. Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Japan;2. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Japan;3. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Japan;4. Department of Surgery, Toho University School of Medicine, Japan;1. Centre de Recherche du CHUM, Montreal, QC, H2X 0A9, Canada;2. Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, H2X 0A9, Canada;3. Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada;4. These authors contributed equally;1. REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal;2. CEBIMED, Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal;3. Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute – Porto, Rua Dr. António Bernardino de Almeida, Porto, Portugal;4. Department of Pathology, Portuguese Oncology Institute – Porto, Rua Dr. António Bernardino de Almeida, Porto, Portugal;5. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal;6. CBQF – Center for Biotechnology and Fine Chemistry – Associated Laboratory, Faculty of Biotechnology, Catholic University of Portugal, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal |
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| Abstract: | AimEpidermal 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).MethodsNormal human epidermal keratinocytes (NHEK) were incubated for 2 and 24 h 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.ResultsA 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).ConclusionsThe 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. |
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| Keywords: | EGFR Erk 1/2 EGFRI Skin toxicity CXCL8/IL-8 Keratinocytes |
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