Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis

Roth-Carter, Quinn R.; Burks, Hope E.; Ren, Ziyou; Koetsier, Jennifer L.; Tsoi, Lam C.; Harms, Paul W.; Xing, Xianying; Kirma, Joseph; Harmon, Robert M.; Godsel, Lisa M.; Perl, Abbey; Gudjonsson, Johann E.; Green, Kathleen J.

doi:10.1172/jci.insight.168955

Cited by 5 publications

(1 citation statement)

References 47 publications

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“…The convergence of these two disorders upon the same signaling pathway explains the similarity of their pathologic features. Moreover, recent RNA sequencing of skin biopsies from patients with Grover or Darier disease identified an overlapping transcriptional signature that pointed to dysregulation of serum response factor and the actin cytoskeleton (44), both of which are modulated by MEK and ERK (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

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

Simpson,

Tiwaa,

Zaver

et al. 2024

Preprint

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Grover disease is an acquired dermatologic disorder characterized by pruritic vesicular and eroded skin lesions. While its pathologic features are well-defined, including impaired cohesion of epidermal keratinocytes, the etiology of Grover disease remains unclear and it lacks any FDA-approved therapy. Interestingly, drug-induced Grover disease occurs in patients treated with B-RAF inhibitors that can paradoxically activate C-RAF and the downstream kinase MEK. We recently identified hyperactivation of MEK and ERK as key drivers of Darier disease, which is histologically identical to Grover disease, supporting our hypothesis that they share a pathogenic mechanism. To model drug-induced Grover disease, we treated human keratinocytes with clinically utilized B-RAF inhibitors dabrafenib or vemurafenib and leveraged a fluorescent biosensor to confirm they activated ERK, which disrupted intercellular junctions and compromised keratinocyte sheet integrity. Consistent with clinical data showing concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed excess ERK activity to rescue cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in skin biopsies of vemurafenib-induced Grover disease, but also in spontaneous Grover disease. In sum, our data define a pathogenic role for ERK hyperactivation in Grover disease and support MEK inhibition as a therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

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

Simpson,

Tiwaa,

Zaver

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Effective treatment of recalcitrant Hailey-Hailey disease with dupilumab

Patel,

Rosenberg,

Cohen

et al. 2025

JAAD Case Reports

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

Simpson,

Tiwaa,

Zaver

et al. 2024

JCI Insight

View full text Add to dashboard Cite

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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Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis

Cited by 5 publications

References 47 publications

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

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

Effective treatment of recalcitrant Hailey-Hailey disease with dupilumab

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

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