EGFR controls skin barrier integrity and microbiota

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 predominance 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.

The epidermal growth factor receptor (EGFR) is a key target in anti-cancer therapies. Its inhibition reduces tumour growth but, due to its biological importance to the skin, also induces skin-related adverse events. These side effects can be so severe that they force the patient to reduce their treatment dose reduction or stop the therapy altogether, even when its proving effective against cancer This project aimed to better understand the biological, structural and immunological functions of EGFR in the skin and to develop supportive care treatment options that could help cancer patients continue their therapy with fewer complications. By improving both treatment outcomes and patients' quality of life, these efforts could make cancer therapies more effective overall. In an international collaboration, the research teams of Thomas Bauer from the Medical University of Vienna, Austria and Bernhard Homey from the University Clinic Düsseldorf, Germany, have identified a promising new therapeutic target. Utilizing a preclinical model of EGFR-deficiency associated inflammation, the Bauer lab screened for dysregulated molecular pathways and could identify that an over-sensitive Janus kinase (JAK) pathway in the hair follicles was driving the skin inflammation. Interestingly, this JAK dependent hair follicle inflammation identified in cancer patients showed remarkable similarities to a condition called scarring alopecia in humans, a distressing disorder that leads to permanent hair loss. The researchers tested JAK inhibitors as a potential treatment in their model, and the results were promising. This approach was then successfully used in the clinic of Bernhard Homey to treat a patient with scarring alopecia who had previously not responded to other treatments. This international project, funded by the Austrian (FWF) and German (DFG) Science Fund therefore is a successful example of precision medicine -where basic research directly leads to new clinical treatments. Future studies now aim to identify the exact molecular mechanisms behind this novel therapy, with the goal of improving its effectiveness and expanding clinical trials to include more patients with various types of scarring alopecia and cancer patients undergoing targeted therapy.