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BRAF Inhibitors for the Treatment of Papulopustular Eruptions from MAPK Pathway Inhibitors

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Abstract

Inhibitors of the mitogen-activated protein kinase (MAPK) pathway are commonly used in clinical oncology. However, with the exception of BRAF inhibitors (BRAFi), MAPK pathway inhibitors such as epidermal growth factor receptor inhibitors (EGFRi) or MEK inhibitors (MEKi) are associated with dose-limiting papulopustular eruptions. Interestingly, patients treated with a combination of systemic BRAFi and MEKi experience less skin toxicities than patients on monotherapy BRAFi or MEKi. The reduction in cutaneous adverse events with combination therapy is thought to be due to a paradoxical activation of the MAPK pathway by BRAFi in keratinocytes carrying wildtype BRAF. Although treatment options for EGFRi- or MEKi-induced papulopustular eruptions exist, many patients still experience dose reduction, interruption, or discontinuation of EGFRi or MEKi. With the goal of activating MAPK signaling in the skin via BRAFi while minimizing systemic risks, we propose topical BRAFi therapy for the treatment and prevention of papulopustular eruptions due to MAPK pathway inhibitors. If effective, patients will be able to tolerate higher doses of MAPK pathway inhibitors, stay on treatment longer, and achieve better therapeutic outcomes overall.

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Authors and Affiliations

  1. Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, 12N240C, Bethesda, MD, 20892-1908, USA

    Catherine J. Wang & Isaac Brownell

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  1. Catherine J. Wang
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  2. Isaac Brownell
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Contributions

CJW performed the literature search, data analysis and drafted the manuscript. IB designed and conceptualized the study and critically revised the manuscript.

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Correspondence to Isaac Brownell.

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Funding

This work was supported by the National Institutes of Health (NIH) Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). This research was also made possible through the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, Genentech, the American Association for Dental Research, the Colgate-Palmolive Company, and other private donors. The opinions expressed are those of the authors and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Catherine J. Wang and Isaac Brownell declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Wang, C.J., Brownell, I. BRAF Inhibitors for the Treatment of Papulopustular Eruptions from MAPK Pathway Inhibitors. Am J Clin Dermatol 21, 759–764 (2020). https://doi.org/10.1007/s40257-020-00539-7

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