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

Abstract

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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/591953v1_figu1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@628b3forg.highwire.dtl.DTLVardef@1a3e4aeorg.highwire.dtl.DTLVardef@fa8875org.highwire.dtl.DTLVardef@14dec1_HPS_FORMAT_FIGEXP M_FIG C_FIG