Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, University "La Sapienza", Rome, Italy.
Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, University "La Sapienza", Rome, Italy; Department of Medical-Surgical Sciences and Translation Medicine, Sant'Andrea Hospital, University "La Sapienza", Rome, Italy.
Eur J Pharmacol. 2019 Nov 5;862:172621. doi: 10.1016/j.ejphar.2019.172621. Epub 2019 Aug 22.
Melanoma onset and progression are associated with a high variety of activating mutations in the MAPK-pathway, most frequently involving BRAF (35-45%) and NRAS (15-25%) genes, but also c-KIT and PTEN. Targeted therapies with BRAF and MEK inhibitors showed promising results over the past years, but it is known that most responses are temporary, and almost all of patients develop a tumor relapse within one year. Different drug-resistance mechanisms underlie the progression of disease and activation of both MAPK and PI3K/AKT/mTOR pathways. Therefore, in this article we reviewed the main studies about clinical effects of several target inhibitors, describing properly the most prominent mechanisms of both intrinsic and acquired resistance. Furthermore, suggestive strategies for overcoming drug resistance and the most recent alternative combination therapies to optimize the use of MAPK pathway inhibitors were also discussed.
黑色素瘤的发生和进展与 MAPK 通路中大量的激活突变有关，最常见的是 BRAF（35-45%）和 NRAS（15-25%）基因，但也涉及 c-KIT 和 PTEN。近年来，BRAF 和 MEK 抑制剂的靶向治疗显示出了有希望的结果，但众所周知，大多数反应是暂时的，几乎所有患者在一年内都会出现肿瘤复发。疾病进展和 MAPK 和 PI3K/AKT/mTOR 通路激活的不同耐药机制是导致这种情况的原因。因此，在本文中，我们回顾了关于几种靶向抑制剂的临床效果的主要研究，详细描述了内在和获得性耐药的最显著机制。此外，还讨论了克服耐药性的建议策略以及最新的联合治疗方案，以优化 MAPK 通路抑制剂的使用。
