EGFR controls skin barrier integrity and microbiota

• Applicant: Professor Dr. Bernhard Homey
• Subject Area: Dermatology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422781646

Tyrosine kinase inhibitors are, together with immunotherapy, among the most promising approaches for modern efficient cancer therapy. In particular inhibitors for the epidermal growth factor receptor (EGFR-I), which are widely used to treat solid tumors such as colorectal and lung cancer, are associated with a high frequency of stigmatizing cutaneous side effects, including a papular pustulous rash, dry skin, pruritus, paronychia, alopecia or aberrant hair growth. Importantly, there is a direct correlation between cancer therapy response and rash severity, indicating that the rash severity correlates with EGFR blockade efficiency. It has been established that cutaneous side effects are caused by the direct inhibition of EGFR signaling in the skin. The majority of human epithelial cancers show an overexpression and/or functional activation of the EGFR, thereby promoting proliferation, anti-apoptosis, angiogenesis, and metastasis. EGFR was selected as one of the first candidates for the development of targeted cancer drugs and up to date various EGFR-inhibitors (EGFR-I) have successfully been established for the treatment of cancer, including non-small cell lung, colorectal, and head-and-neck cancer. Whereas EGFR-I therapy is effective, its feasibility is limited by characteristic side effects that affect patients` quality of life (QoL) and bear a severe threat for therapy adherence. Of note, the pre¬dominance of cutaneous side effects reflects the central function of the EGFR for the skin. Characteristic papulopustular rashes are the most frequent adverse effect of EGFR-I and develop in 60-90% of the patients.A team of dermatologists from Germany and a team of immunologists from Austria could recently clarify the events induced by EGFR-I in the skin. The hallmarks of the epidermal inflammation could be identified as a barrier disruption at the hair follicle followed by a bacterial invasion. The present project aims to clarify the mechanisms behind the breakdown of the skin barrier and the anti-microbial defense, identify the responsible microorganisms and characterize in detail the compositional shifts in the skin microbiota.Understanding the mechanistic details of the events following EGFR inhibition in the skin of cancer patients, will not only significantly advance our knowledge of the central function of EGFR for the skin but may furthermore identify new therapeutic targets for prevention and management of EGFR-I induced adverse effects. This may not only lead to an improved QoL for cancer patients but may eventually enable intensified anti-cancer therapy.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Cooperation Partner: Dr. Thomas Bauer, Ph.D.
• Co-Investigator: Dr. Bettina Alexandra Buhren