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Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

Medical Center, Department of Dermatology, University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
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Author to whom correspondence should be addressed.
Academic Editor: Alvaro Teijeira
Int. J. Mol. Sci. 2021, 22(18), 9890; https://doi.org/10.3390/ijms22189890
Received: 11 August 2021 / Revised: 8 September 2021 / Accepted: 10 September 2021 / Published: 13 September 2021
(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)
The advent of mitogen-activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non-tumor cells. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non-intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment. View Full-Text
Keywords: BRAF; MEK; targeted therapy; immunological effects; immune checkpoint inhibitors; metastatic melanoma; CTLA-4; PD-1; PD-L1; paradoxical ERK activation; inflammasome; tumor microenvironment BRAF; MEK; targeted therapy; immunological effects; immune checkpoint inhibitors; metastatic melanoma; CTLA-4; PD-1; PD-L1; paradoxical ERK activation; inflammasome; tumor microenvironment
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MDPI and ACS Style

Jung, T.; Haist, M.; Kuske, M.; Grabbe, S.; Bros, M. Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond. Int. J. Mol. Sci. 2021, 22, 9890. https://doi.org/10.3390/ijms22189890

AMA Style

Jung T, Haist M, Kuske M, Grabbe S, Bros M. Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond. International Journal of Molecular Sciences. 2021; 22(18):9890. https://doi.org/10.3390/ijms22189890

Chicago/Turabian Style

Jung, Thomas, Maximilian Haist, Michael Kuske, Stephan Grabbe, and Matthias Bros. 2021. "Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond" International Journal of Molecular Sciences 22, no. 18: 9890. https://doi.org/10.3390/ijms22189890

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