Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.
Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.
Nat Rev Urol. 2022 May;19(5):305-320. doi: 10.1038/s41585-022-00571-8. Epub 2022 Mar 9.
The treatment of advanced and metastatic kidney cancer has entered a golden era with the addition of more therapeutic options, improved survival and new targeted therapies. Tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint blockade have all been shown to be promising strategies in the treatment of renal cell carcinoma (RCC). However, little is known about the best therapeutic approach for individual patients with RCC and how to combat therapeutic resistance. Cancers, including RCC, rely on sustained replicative potential. The cyclin-dependent kinases CDK4 and CDK6 are involved in cell-cycle regulation with additional roles in metabolism, immunogenicity and antitumour immune response. Inhibitors of CDK4 and CDK6 are now commonly used as approved and investigative treatments in breast cancer, as well as several other tumours. Furthermore, CDK4/6 inhibitors have been shown to work synergistically with other kinase inhibitors, including mTOR inhibitors, as well as with immune checkpoint inhibitors in preclinical cancer models. The effect of CDK4/6 inhibitors in kidney cancer is relatively understudied compared with other cancers, but the preclinical studies available are promising. Collectively, growing evidence suggests that targeting CDK4 and CDK6 in kidney cancer, alone and in combination with current therapeutics including mTOR and immune checkpoint inhibitors, might have therapeutic benefit and should be further explored.
随着更多治疗选择的出现、生存时间的延长和新的靶向治疗药物的问世，晚期和转移性肾细胞癌的治疗已经进入了一个黄金时代。酪氨酸激酶抑制剂、哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂和免疫检查点抑制剂在肾细胞癌（RCC）的治疗中均显示出良好的疗效。然而，对于 RCC 患者，我们还知之甚少，尚不清楚哪种治疗方法最适合特定的患者，以及如何对抗治疗耐药性。包括 RCC 在内的各种癌症都依赖于持续的复制潜能。细胞周期蛋白依赖性激酶 CDK4 和 CDK6 参与细胞周期的调控，同时在代谢、免疫原性和抗肿瘤免疫反应中也发挥作用。CDK4 和 CDK6 抑制剂目前已被广泛用于乳腺癌和其他几种肿瘤的批准治疗和研究性治疗。此外，在临床前癌症模型中，CDK4/6 抑制剂已被证明与其他激酶抑制剂（包括 mTOR 抑制剂）以及免疫检查点抑制剂具有协同作用。与其他癌症相比，肾细胞癌中 CDK4/6 抑制剂的研究相对较少，但目前的临床前研究结果很有前景。综上所述，越来越多的证据表明，单独或联合目前的治疗药物（包括 mTOR 和免疫检查点抑制剂）靶向 CDK4 和 CDK6 在肾细胞癌中可能具有治疗益处，值得进一步探索。
