دورية أكاديمية
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.
| العنوان: | 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. |
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| المؤلفون: | Ondet T; SkinCare R&D, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France., Roux PF; SkinCare R&D, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France., Monshouwer M; Discovery Sciences, Janssen Pharmaceutical Research and Development, Beerse, Belgium., Stamatas GN; SkinCare R&D, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France. |
| المصدر: | JID innovations : skin science from molecules to population health [JID Innov] 2021 Mar 06; Vol. 1 (2), pp. 100009. Date of Electronic Publication: 2021 Mar 06 (Print Publication: 2021). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier B.V. on behalf of the Society for Investigative Dermatology Country of Publication: Netherlands NLM ID: 101776173 Publication Model: eCollection Cited Medium: Internet ISSN: 2667-0267 (Electronic) Linking ISSN: 26670267 NLM ISO Abbreviation: JID Innov Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: {Amsterdam] : Elsevier B.V. on behalf of the Society for Investigative Dermatology, [2021]- |
| مستخلص: | 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. (© 2021 The Authors.) |
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| فهرسة مساهمة: | Keywords: 1,25(OH)2VD3, 1,25-dihydroxyvitamine D3; AFA, afatinib; Akt, protein kinase B; C, cluster; CADR, cutaneous adverse drug reaction; CYP, cytochrome P450; EGFRi, EGFR inhibitor; K, keratin; KC, keratinocyte; LCE, late cornified envelope; PI3K, phosphatidylinositol 3-kinase; RHE, reconstructed human epidermis; TKI, tyrosine kinase inhibitor; Th, T helper type; VD3, vitamin D3 |
| تواريخ الأحداث: | Date Created: 20211215 Latest Revision: 20211217 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC8659385 |
| DOI: | 10.1016/j.xjidi.2021.100009 |
| PMID: | 34909713 |
| قاعدة البيانات: | MEDLINE |
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