表皮角质细胞中的ERK过度激活会损害细胞间粘附力,并驱动格罗弗病的病理变化。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson
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引用次数: 0

摘要

格罗弗病是一种获得性表皮水疱病,角质细胞失去细胞间连接。虽然其病理特征已明确,但病因仍不清楚,也缺乏任何经 FDA 批准的治疗方法。有趣的是,在使用B-RAF抑制剂的癌症临床试验中,格罗弗病是一种常见的不良事件,但B-RAF阻断如何损害皮肤完整性仍是未知数。在这里,我们确定ERK过度激活是Grover病病理学的关键驱动因素。我们利用荧光生物传感器证实,B-RAF抑制剂达拉非尼和维莫非尼在人类角朊细胞和有机表皮中激活了ERK,破坏了细胞-细胞连接,削弱了上皮的完整性。临床数据显示,同时使用 MEK 阻断剂可预防接受 B-RAF 抑制剂治疗的患者出现格罗弗病,与此相一致,我们发现 MEK 抑制剂抑制了 ERK,并挽救了受 B-RAF 抑制的角朊细胞的内聚力。为了验证这些结果,我们在维莫非尼诱导的格罗弗病和自发性格罗弗病的患者活检组织中发现了ERK过度激活现象,揭示了两者的共同病因。最后,我们的研究发现,这两种疾病的致病机制都与ERK信号转导有关,并支持将MEK抑制作为一种治疗策略。.
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology.

Grover disease is an acquired epidermal blistering disorder in which keratinocytes lose intercellular connections. While its pathologic features are well defined, its etiology remains unclear, and there is no FDA-approved therapy. Interestingly, Grover disease was a common adverse event in clinical trials for cancer using B-RAF inhibitors, but it remained unknown how B-RAF blockade compromised skin integrity. Here, we identified ERK hyperactivation as a key driver of Grover disease pathology. We leveraged a fluorescent biosensor to confirm that the B-RAF inhibitors dabrafenib and vemurafenib paradoxically activated ERK in human keratinocytes and organotypic epidermis, disrupting cell-cell junctions and weakening epithelial integrity. Consistent with clinical data showing that concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed ERK and rescued cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in patient biopsies from vemurafenib-induced Grover disease and from spontaneous Grover disease, revealing a common etiology for both. Finally, in line with our recent identification of ERK hyperactivation in Darier disease, a genetic disorder with identical pathology to Grover disease, our studies uncovered that the pathogenic mechanisms of these diseases converge on ERK signaling and support MEK inhibition as a therapeutic strategy.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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