Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Tailored Therapeutics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Pharmacol Ther. 2015 May;149:139-49. doi: 10.1016/j.pharmthera.2014.12.003. Epub 2014 Dec 27.
Selective BRAF inhibitors have demonstrated significant clinical benefit in melanoma patients harboring oncogenic BRAF mutations. However, the majority of such patients either exhibit de novo resistance from the beginning of the treatment or acquire resistance and eventually relapse. Despite tremendous progress in understanding the underlying mechanisms of resistance, overcoming resistance to BRAF inhibitors remains an unmet medical need. Constitutive activation of cyclin-dependent kinases (CDK) 4/6 as a result of genetic aberrations including CDKN2A inactivation and CCND1 amplification is common across many cancer types and frequently co-occurs with oncogenic BRAF mutations. Also, cyclin D1 overexpression is a common feature of resistance to BRAF inhibitors. Here we review CDK4/6 as a therapeutic target in BRAF mutant cancers and discuss emerging evidence supporting a critical role of cyclin D1/CDK4/6 axis in de novo and acquired resistance to BRAF inhibitors. Co-targeting CDK4/6 and BRAF could be a more effective therapy to augment clinical response of BRAF inhibitors and overcome resistance in BRAF mutant cancers.
选择性 BRAF 抑制剂已在携带致癌 BRAF 突变的黑色素瘤患者中显示出显著的临床获益。然而，大多数此类患者要么从治疗开始就表现出原发性耐药，要么获得耐药并最终复发。尽管在理解耐药的潜在机制方面取得了巨大进展，但克服 BRAF 抑制剂的耐药性仍然是一个未满足的医疗需求。包括 CDKN2A 失活和 CCND1 扩增在内的遗传异常导致的细胞周期蛋白依赖性激酶 (CDK) 4/6 的组成性激活在许多癌症类型中很常见，并且经常与致癌 BRAF 突变同时发生。此外，细胞周期蛋白 D1 的过表达是对 BRAF 抑制剂耐药的常见特征。在这里，我们回顾了 CDK4/6 作为 BRAF 突变型癌症的治疗靶点，并讨论了支持细胞周期蛋白 D1/CDK4/6 轴在 BRAF 抑制剂原发性和获得性耐药中的关键作用的新证据。联合靶向 CDK4/6 和 BRAF 可能是一种更有效的治疗方法，可增强 BRAF 抑制剂的临床反应并克服 BRAF 突变型癌症的耐药性。
