Elucidation of the pathogenic mechanism of acneiform skin eruptions caused by molecular targeted drugs

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17357
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Nara Medical University
• Principal Investigator: Ommori Rie 奈良県立医科大学, 医学部, 特任助教 (20533722)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: human β-defensin / 抗菌ペプチド / 自然免疫応答 / 分子標的治療薬 / EGFR阻害薬 / ざ瘡様皮疹 / 薬疹

Outline of Final Research Achievements

EGFR inhibitors (EGFRIs) are a well-established targeted therapy for several cancers, and these drugs frequently cause cutaneous adverse effects such as acneiform eruptions. However, the mechanism of the reactions remains unclear. In the present study, we investigated whether EGFRIs have an influence on innate immune response in patients’ skin to reveal the pathological mechanism of cutaneous adverse reactions caused by EGFRIs. In this study, we found that human β-defensin (hBD) was significantly decreased in patients with acneiform eruptions. S. epidermidis induced the expression of TGF-α in a TLR2-dependent manner, and subsequently produced hBD3 through EGFR signaling. EGFR signaling is necessary for hBD3 production induced by S. epidermidis. Our results suggest that S. epidermidis induce the expression of hBD3 via EGFR by inducing TGF-α under normal condition, but in patients treated with EGFRIs, hBD3 expression is significantly decreased, resulting in acneiform eruptions.

Free Research Field

皮膚科学

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、EGFR阻害薬によるざ瘡様皮疹の発症にはβ-defensinの低下が密接に関与いる可能性が示唆された。平時ではブドウ球菌の感染はTGF-αとの相乗効果によりβ-defensinの発現を誘導することで、自然免疫応答を維持しているが、EGFR阻害剤を投与された患者においてはβ-defensin発現が著明に低下し、ざ瘡様皮疹が生じるのではないかと考えられた。