Thompson Elizabeth L, Hu Jiayi J, Niedernhofer Laura J
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA.
Cancers (Basel). 2021 May 7;13(9):2241. doi: 10.3390/cancers13092241.
is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma.
是恶性黑色素瘤中最常见的突变基因，主要是激酶结构域中密码子600的错义突变。这种致癌性错义突变导致丝裂原活化蛋白激酶（MAPK）促生存途径的组成性激活。已经开发了几种BRAF抑制剂（BRAFi）来特异性抑制改善黑色素瘤生存的突变，但耐药性和继发性癌症经常发生。通过MAPK和替代促生存途径的上调，已经确定了BRAFi诱导继发性癌症和耐药性的因果机制。此外，在从良性痣到恶性黑色素瘤的疾病进展过程中，观察到细胞衰老的超越。在这篇综述中，我们讨论黑色素瘤突变、BRAFi耐药的遗传机制，以及支持衰老细胞在黑色素瘤疾病进展、耐药性和继发性癌症中作用的证据。我们进一步强调了用衰老疗法靶向衰老细胞作为辅助治疗对抗黑色素瘤的潜在益处。
