International Journal of Molecular Sciences | |
Targeted Therapy in Melanoma and Mechanisms of Resistance | |
Anna M. Czarnecka1  Piotr Rutkowski1  Ewa Bartnik2  Michał Fiedorowicz3  | |
[1] Department of Soft Tissue/Bone, Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland;Small Animal Magnetic Resonance Imaging Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland; | |
关键词: BRAF; MEK; melanoma; MAPK; drug resistance; | |
DOI : 10.3390/ijms21134576 | |
来源: DOAJ |
【 摘 要 】
The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).
【 授权许可】
Unknown