Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson
{"title":"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。","authors":"Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson","doi":"10.1172/jci.insight.182983","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology.\",\"authors\":\"Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson\",\"doi\":\"10.1172/jci.insight.182983\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":14722,\"journal\":{\"name\":\"JCI insight\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.3000,\"publicationDate\":\"2024-11-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JCI insight\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1172/jci.insight.182983\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCI insight","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/jci.insight.182983","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
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.
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.