Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms22189890
Keywords
BRAF; MEK; targeted therapy; immunological effects; immune checkpoint inhibitors; metastatic melanoma; CTLA-4; PD-1; PD-L1; paradoxical ERK activation; inflammasome; tumor microenvironment
Funding
- Deutsche Forschungsgemeinschaft [SFB1066]
- Else Kroner Fresenius Foundation
- University Medical Center Mainz
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The advent of MAPK inhibitors and ICI has greatly improved the treatment of metastatic melanoma, with BRAF/MEK inhibitors used for BRAF mutation patients, showing immunomodulatory functions in addition to their antiproliferative effects.
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.
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