ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology.

ABSTRACT: 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 M

SUBMITTER: Simpson CL 

PROVIDER: S-EPMC11601706 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature