Unlocking the Mechanisms of Cutaneous Adverse Drug Reactions: Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway by EGFR Inhibitors Triggers Keratinocyte Differentiation and Polarization of Epidermal Immune Responses
| Autor: | Georgios N. Stamatas, Thomas Ondet, Mario Monshouwer, Pierre-François Roux |
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| Rok vydání: | 2020 |
| Předmět: |
Th
T helper type medicine.drug_class Afatinib 1 25(OH)2VD3 1 25-dihydroxyvitamine D3 CADR cutaneous adverse drug reaction Dermatology LCE late cornified envelope TKI tyrosine kinase inhibitor Tyrosine-kinase inhibitor chemistry.chemical_compound medicine Phosphatidylinositol RHE reconstructed human epidermis Protein kinase B PI3K/AKT/mTOR pathway VD3 vitamin D3 EGFR inhibitors EGFRi EGFR inhibitor AFA afatinib Chemistry Kinase KC keratinocyte PI3K phosphatidylinositol 3-kinase K keratin medicine.anatomical_structure RL1-803 Akt protein kinase B Cancer research CYP cytochrome P450 Original Article C cluster Keratinocyte medicine.drug |
| Zdroj: | JID Innovations JID Innovations, Vol 1, Iss 2, Pp 100009-(2021) |
| ISSN: | 2667-0267 |
| Popis: | EGFR inhibitors used in oncology therapy modify the keratinocyte differentiation processes, impairing proper skin barrier formation and leading to cutaneous adverse drug reactions. To uncover the molecular signatures associated with cutaneous adverse drug reactions, we applied phosphoproteomic and transcriptomic assays on reconstructed human epidermis tissues exposed to a therapeutically relevant concentration of afatinib, a second-generation EGFR inhibitor. After drug exposure, we observed activation of the phosphatidylinositol 3-kinase/protein kinase B pathway associated with an increased expression of gene families involved in keratinocyte differentiation, senescence, oxidative stress, and alterations in the epidermal immune-related markers. Furthermore, our results show that afatinib may interfere with vitamin D3 metabolism, acting via CYP27A1 and CYP24A1 to regulate calcium concentration through the phosphatidylinositol 3-kinase/protein kinase B pathway. Consequently, basal layer keratinocytes switch from a pro-proliferating to a prodifferentiative program, characterized by upregulation of biomarkers associated with increased keratinization, cornification, T helper type 2 response, and decreased innate immunity. Such effects may increase skin susceptibility to cutaneous penetration of irritants and pathogens. Taken together, these findings demonstrate a molecular mechanism of EGFR inhibitor–induced cutaneous adverse drug reactions. |
| Databáze: | OpenAIRE |
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