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Mechanisms of skin aging induced by EGFR inhibitors

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Abstract

Background

The mechanisms of skin aging have not been completely elucidated. Anecdotal data suggests that EGFR inhibition accelerates aging-like skin changes.

Objective

The objective of the study was to evaluate the clinical characteristics and investigate the cellular and molecular mechanisms underlying skin changes associated with the use of EFGRIs.

Patients and methods

Patients during prolonged treatment with EGFRIs (>3 months) were analyzed for aging-like skin changes. Baseline EGFR expression was compared in young (<25 years old) vs. old (> 65 years old) skin. In addition, the regulation of extracellular matrix, senescence-associated genes, and cell cycle status was measured in primary human keratinocytes treated with erlotinib in vitro.

Results

There were progressive signs of skin aging, including xerosis cutis, atrophy, rhytide formation, and/or actinic purpura in 12 patients. Keratinocytes treated with erlotinib in vitro showed a significant down-modulation of hyaluronan synthases (HAS2 and HAS3), whereas senescence-associated genes (p21, p53, IL-6, maspin) were upregulated, along with a G1 cell cycle arrest and stronger SA β-Gal activity. There was significantly decreased baseline expression in EGFR density in aged skin, when compared to young controls.

Conclusions

EGFR inhibition results in molecular alterations in keratinocytes that may contribute to the observed skin aging of patients treated with respective targeted agents.

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Abbreviations

AE:

adverse event

ECM:

extracellular matrix

EGFRI:

epidermal growth factor (EGF) receptor (EGFR) inhibitor

HAS:

hyaluronan (HA) synthase

IL:

interleukin

MSKCC:

Memorial Sloan Kettering Cancer Center

PCR:

polymerase chain reaction

ROS:

reactive oxygen species

SA β-Gal:

senescence-associated β-galactosidase

SASP:

senesence-associated secretory phenotype

TGF:

transforming growth factor

TNF:

tumor necrosis factor

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Author information

Authors and Affiliations

  1. Department of Dermatology, Medical Faculty, University of Düsseldorf, Moorenstrasse 5, D-40225, Duesseldorf, Germany

    Peter Arne Gerber, Bettina Alexandra Buhren, Holger Schrumpf, Peter Hevezi & Bernhard Homey

  2. Clinic and Polyclinic, Radiation Therapy and Radiooncology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany

    Edwin Bölke

  3. Laboratory of Molecular Radiooncology, Radiation Therapy and Radiooncology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany

    Dennis Sohn & Reiner U. Jänicke

  4. Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Viswanath Reddy Belum & Mario E. Lacouture

  5. Dermatology Service and Paris-Sud University, Gustave Roussy Cancer Campus, Villejuif-Paris Sud, Paris, France

    Caroline Robert

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  1. Peter Arne Gerber
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Corresponding author

Correspondence to Peter Arne Gerber.

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Conflict of interest

BAB, HS, PH, EB, DS, VRB, and CR have no conflicts of interest to declare; PAG has a speaking, consultant or advisory role with Amgen, Galderma, and Roche; MEL has a speaking, consultant or advisory role with Advancell, Amgen, AstraZeneca, Augmentium, Aveo, Bayer, Berg Pharma, Biopharm Communications, Boehringer Ingelheim, Brickell Biotech, Bristol-Myers Squibb, Clinical Assistance Programs, Clinical Care Options, EMD Serono, Envision Communications, Foamix, Galderma, Genentech, GlaxoSmithKline, Helsinn, Institute for Medical Education and Research, Integro-MC, Lindi Skin, Medscape, Medtrend International, Merck, Nerre Therapeutics, Novartis, Novocure, Oncology Specialty Group, OSI Pharmaceuticals, Permanyer, Physicians Education Resource, Pierre Fabre, Pfizer, Reata Pharmaceuticals, Roche, Sandoz, Sanofi Aventis, and Threshold Pharmaceuticals.

Funding

This work was supported by a grant of the Duesseldorf Science Commission and a grant by Roche Pharmaceuticals. MEL was funded in part through the NIH/Cancer Center Support Grant P30 CA008748.

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The contents of this manuscript have not been presented, and are not under consideration for publication elsewhere.

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Gerber, P.A., Buhren, B.A., Schrumpf, H. et al. Mechanisms of skin aging induced by EGFR inhibitors. Support Care Cancer 24, 4241–4248 (2016). https://doi.org/10.1007/s00520-016-3254-7

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  • DOI: https://doi.org/10.1007/s00520-016-3254-7

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