Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy-Paradoxical ERK Activation and Beyond.
Thomas JungMaximilian HaistMichael KuskeStephan GrabbeMatthias BrosPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- ejection fraction
- pi k akt
- signaling pathway
- metastatic colorectal cancer
- wild type
- cell proliferation
- oxidative stress
- healthcare
- sars cov
- chronic kidney disease
- dendritic cells
- end stage renal disease
- stem cells
- cell therapy
- regulatory t cells
- risk assessment
- newly diagnosed
- drug delivery
- prognostic factors
- patient reported outcomes