biostudies-literatureSimpson CLNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNCATS NIH HHSFoundation for Ichthyosis and Related Skin TypesPhysician-Scientist Support FundTaubman Medical Research InstituteNIAMS NIH HHSUniversity of Washington Institute for Stem Cell and Regenerative Medicinee182983https://www.ebi.ac.uk/biostudies/studies/S-EPMC11601706biostudies-literatureUnknown9(21)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 MJCI insightERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology.PMC11601706N/AP30 AR069589NIH P30-AR069589Innovation Pilot AwardR03 TR005428NIH R03-AR082896Research GrantK08 AR075846NIH K08-AR075846NIH P30-AR075043R03 AR082896Medical Scholars Research FellowshipP30 AR075043Tiwaa AGudjonsson JEHarms PWSimpson CLZaver SAChu EYJohnson CJfalseERK 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 M2024-01-01T00:00:00Z2024 Nov2025-04-04T02:39:00.895Z2025-04-04T02:39:00.895ZS-EPMC116017063932554110.1172/jci.insight.182983