Lee Belinda, Sandhu Shahneen, McArthur Grant
aDepartment of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne bDepartment of Pathology, University of Melbourne, Parkville cDepartment of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy dMolecular Oncology Laboratory, Oncogenic Signalling and Growth Control Program eTranslational Research Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Curr Opin Oncol. 2015 Mar;27(2):141-50. doi: 10.1097/CCO.0000000000000159.
This review highlights recent clinical developments in the therapeutic targeting of cell cycle control in melanoma with cyclin-dependent kinase inhibitors, checkpoint kinases, MDM2, MDM4 and p53 inhibitors.
The high prevalence of activating genetic aberrations along the p16 INK4A:cyclinD-CDK4/6:RB pathway in melanoma and increasing evidence that alterations in this pathway are linked to melanomagenesis, make targeting the p16 INK4A:cyclinD-CDK4/6:RB pathway in melanoma logical and highly attractive. The presence of elevated CDK4 activity appears to correlate with greater CDK4/6 inhibitor therapeutic activity, whereas the loss of RB1 has been linked to CDK inhibitor resistance. Other novel compounds targeting cell cycle control via reactivating wild-type p53 and checkpoint kinases are also currently under investigation in melanoma.
Cell cycle control is a promising target in the management of melanoma with early data reporting therapeutic benefit with cyclin-dependent kinase inhibitors, MDM2, and p53 reactivation compounds. Many of these drugs have entered phase I and II clinical trial development. Preliminary data from these studies are discussed in this review along with future treatment strategies for maximizing treatment outcomes in advanced melanoma.
本综述重点介绍了黑色素瘤细胞周期调控治疗靶点的最新临床进展，包括细胞周期蛋白依赖性激酶抑制剂、检查点激酶、MDM2、MDM4和p53抑制剂。
黑色素瘤中p16 INK4A:细胞周期蛋白D-CDK4/6:RB通路激活型基因畸变的高发生率，以及越来越多的证据表明该通路的改变与黑色素瘤发生有关，使得靶向黑色素瘤中的p16 INK4A:细胞周期蛋白D-CDK4/6:RB通路具有合理性且极具吸引力。CDK4活性升高似乎与更高的CDK4/6抑制剂治疗活性相关，而RB1缺失与CDK抑制剂耐药有关。目前也正在黑色素瘤中研究其他通过重新激活野生型p53和检查点激酶来靶向细胞周期调控的新型化合物。
细胞周期调控是黑色素瘤治疗中一个有前景的靶点，早期数据报告了细胞周期蛋白依赖性激酶抑制剂、MDM2和p53重新激活化合物的治疗益处。其中许多药物已进入I期和II期临床试验开发阶段。本综述讨论了这些研究的初步数据以及晚期黑色素瘤最大化治疗效果的未来治疗策略。
