Yale Researchers Repurpose Cancer Drug Erlotinib for Rare Genetic Skin Disorder
Key Insights
Yale researchers identified a recurrent mutation in the EMP2 (search) gene causing a rare form of ichthyosis (search) with severely thickened, red, and scaly skin.
Single-cell spatial transcriptomics revealed that EGFR (search) pathways failed to turn off during skin differentiation in affected patients.
Treatment with erlotinib (Tarceva), an EGFR (search) inhibitor originally developed for cancer, led to resolution of skin disease at many sites.
Yale researchers have successfully repurposed a cancer drug to treat a rare genetic skin disorder, demonstrating the potential of precision medicine approaches for orphan diseases. The study, published August 4 in PNAS, found that erlotinib (Tarceva), an EGFR (search) inhibitor originally developed for cancer treatment, effectively resolved skin lesions in patients with a previously undescribed form of ichthyosis (search).
Novel Genetic Discovery
The research team, led by Keith Choate, MD, PhD, Aaron B. and Marguerite Lerner Professor and Chair of Dermatology at Yale, identified a recurrent mutation in the EMP2 (search) gene that causes a severe skin disorder in the progressive symmetric erythrokeratoderma (search) spectrum. The condition is characterized by severely thickened, red, and scaly skin at sites of wound healing or repetitive movement, including the face, genitals, flexural areas, and the palms and soles.
Working with postdoctoral fellow Xingyuan Jiang, MD, MBBS, and MD-PhD student Ryland Mortlock, the team discovered that the mutation arises uniquely in affected individuals but is not present in their parents. The EMP2 (search) gene encodes epithelial membrane protein 2, a cell surface tetraspan protein in the growth-arrest specific 3 (GAS3)/peripheral myelin protein 22 (PMP22) family.
Mechanistic Insights Through Advanced Genomics
The researchers employed single-cell spatial transcriptomics to study gene expression patterns in affected skin tissue. This analysis revealed a critical dysfunction in normal skin differentiation processes. In healthy skin, cells proliferate in the basal layer before stopping proliferation and undergoing differentiation to form a protective barrier against water loss.
However, in patients with the EMP2 (search) mutation, pathways typically activated in proliferating cells downstream of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR (search)), failed to appropriately turn off during differentiation. This finding provided the scientific rationale for targeting EGFR as a therapeutic approach.
The connection between EMP2 (search) and cellular signaling pathways stems from previous research showing that EMP2 directly associates with focal adhesion kinase (FAK (search)), which links cell junction forces to signaling pathways relevant to proliferation, migration, and wound healing.
Therapeutic Success with Drug Repurposing
Based on their mechanistic findings, the research team treated patients with erlotinib, an EGFR (search) inhibitor marketed as Tarceva for cancer treatment. The targeted therapy led to resolution of skin disease at many sites, validating their hypothesis about the underlying pathophysiology.
"This study underscores the power of human genetics to reveal previously unknown functions for genes in the skin, setting the stage for development of new therapeutics," said Choate.
Research Support and Implications
The research was supported by the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (award R01AR068392) and Yale University. The findings highlight how genetic discoveries can rapidly translate into therapeutic interventions through drug repurposing, potentially offering hope for patients with rare genetic disorders who have limited treatment options.
The study represents a successful example of precision medicine, where understanding the specific genetic and molecular mechanisms of disease enables targeted therapeutic interventions using existing approved medications.