EGFR controls skin barrier integrity and microbiota

酪氨酸激酶抑制剂与免疫疗法一起，是现代有效癌症治疗最有前途的方法之一。尤其是被广泛用于治疗结直肠癌和肺癌等实体肿瘤的表皮生长因子受体(EGFR-I)的抑制剂，与高频率的污名化皮肤副作用有关，包括丘疹脓疱疹、皮肤干燥、瘙痒、甲旁症、脱发或毛发异常生长。重要的是，癌症治疗反应与皮疹严重程度直接相关，表明皮疹严重程度与EGFR阻断效率相关。已经证实，皮肤副作用是由皮肤中EGFR信号的直接抑制引起的。大多数人类上皮性肿瘤表现出EGFR的过度表达和/或功能激活，从而促进增殖、抗凋亡、血管生成和转移。EGFR被选为开发靶向抗癌药物的首选候选药物之一，到目前为止，已成功地建立了各种EGFR抑制剂(EGFR-I)用于治疗癌症，包括非小细胞肺癌、结直肠癌和头颈癌。尽管EGFR-I疗法是有效的，但其可行性受到特有副作用的限制，这些副作用影响患者的生活质量，并对治疗的依从性构成严重威胁。值得注意的是，主要的皮肤副作用反映了EGFR对皮肤的中心功能。特征性丘疹是EGFR-I最常见的不良反应，在60%-90%的患者中发生。来自德国的皮肤科医生团队和奥地利的免疫学家团队最近可以澄清EGFR-I在皮肤中引发的事件。表皮炎症的特征可以确定为毛囊屏障破裂，随后是细菌入侵。本项目旨在阐明皮肤屏障破坏和抗微生物防御的机制，确定负责的微生物，并详细描述皮肤微生物的组成变化。了解癌症患者皮肤中EGFR抑制后发生的事件的机制细节，不仅将极大地促进我们对EGFR对皮肤的中心功能的了解，而且可能进一步确定预防和管理EGFR-I不良反应的新的治疗靶点。这不仅可能改善癌症患者的生活质量，而且最终可能使强化抗癌治疗成为可能。

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.