Department of Soft Tissue/Bone, Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.
Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
Int J Mol Sci. 2020 Jun 27;21(13):4576. doi: 10.3390/ijms21134576.
The common mutation 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).
常见的原发性黑色素瘤突变会激活丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路，原癌基因 B-Raf（BRAF）和丝裂原活化蛋白激酶激酶（MEK）抑制剂（BRAFi 和 MEKi）的引入是这些癌症治疗的突破。然而，15-20%的肿瘤对这种治疗具有原发性耐药性，此外，患者对治疗产生获得性耐药性。为了开发新的靶向治疗方法，了解 BRAFi/MEKis 耐药背后的分子现象是必不可少的。最常见的是，由于 MAPK/ERK 通路的重新激活或替代激酶信号通路的激活，包括磷酸酶和张力蛋白同系物（PTEN）、神经纤维瘤 1（NF-1）或 RAS 信号，导致对 BRAFi/MEKis 的耐药性发展。酪氨酸激酶受体的过度激活，如血小板衍生生长因子β（PDGFRβ）受体、胰岛素样生长因子 1 受体（IGF-1R）和肝细胞生长因子受体（HGF），导致 AKT/3-磷酸肌醇激酶（PI3K）通路的诱导。导致 BRAFi/MEKi 耐药性的另一条通路是表皮生长因子受体（EGFR）信号的过度激活或小眼畸形相关转录因子（MITF）的失调。
