Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California.
Pfizer Oncology, San Diego, California.
Clin Cancer Res. 2015 Jul 1;21(13):2905-10. doi: 10.1158/1078-0432.CCR-14-0816. Epub 2015 May 4.
Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy.
癌细胞绕过有丝分裂细胞周期进程的正常控制，以实现不受调节的增殖状态。视网膜母细胞瘤肿瘤抑制蛋白（pRb）调控着一个关键的细胞周期检查点，该检查点通常可防止在没有适当有丝分裂信号的情况下，G1 期细胞进入 S 期。癌细胞通常通过组成性磷酸化和与 D 型细胞周期蛋白结合的细胞周期蛋白依赖性激酶（CDK）4 或 CDK6 对 pRb 功能的失活来克服 pRb 依赖性生长抑制。三种选择性 CDK4/6 抑制剂，帕博西利（哌柏西利；辉瑞）、瑞博西利（诺华）和阿贝西利（礼来），正处于不同的研发阶段，用于治疗多种 pRb 阳性肿瘤类型，包括乳腺癌、黑色素瘤、脂肪肉瘤和非小细胞肺癌。迄今为止获得的令人振奋的阳性临床数据最终验证了 20 年来的假说，即细胞周期蛋白 D-CDK4/6 途径是癌症治疗的合理靶点。
