Background: Despite significant progress, prostate cancer remains a leading cause of death. Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are already approved for the treatment of hormone receptor-positive breast cancer, are undergoing extensive testing as monotherapy and in various combinations as a potentially valuable treatment modality in prostate cancer patients. Thus far, a limited number of these studies have published results, which have been largely disappointing. Areas Covered: In this review, we describe the biologic rationale for the use of CDK4/6 inhibitors in prostate cancer, the existing clinical data describing their use in prostate cancer, and ongoing clinical trials of CDK4/6 inhibitors as monotherapy and in combination for the treatment of prostate cancer. In particular, we focus on possible resistance mechanisms that may be particularly relevant in prostate cancer patients, leading to de novo and acquired resistance, and we highlight novel strategies that can overcome this resistance. Conclusions: Current clinical trials are actively working to (1) refine the role of CDK4/6 inhibitors in prostate cancer patients; (2) develop new inhibitors of other cell-cycle targets, such as CDK2 and CDK7; and (3) explore novel combination therapies with inhibitors of other relevant pathways, such as PI3K or MAPK. Further genomic subtyping of advanced prostate cancer will likely shed light on the subsets of patients most likely to benefit from cell-cycle-targeted agents.
背景：尽管已取得显著进展，前列腺癌仍是导致死亡的主要原因之一。细胞周期蛋白依赖性激酶（CDK）4/6抑制剂已被批准用于治疗激素受体阳性乳腺癌，目前正作为单药疗法或多种联合方案在前列腺癌患者中进行广泛测试，有望成为有价值的治疗手段。迄今为止，仅有少数相关研究公布了结果，且大多不尽如人意。 研究领域：本综述阐述了CDK4/6抑制剂用于前列腺癌治疗的生物学原理、现有临床数据以及CDK4/6抑制剂单药及联合治疗前列腺癌的临床试验进展。特别聚焦于前列腺癌患者中可能导致原发性和获得性耐药的相关耐药机制，并重点探讨克服此类耐药的新策略。 结论：当前临床试验正积极推进以下方向：（1）明确CDK4/6抑制剂在前列腺癌患者中的治疗定位；（2）开发针对其他细胞周期靶点（如CDK2和CDK7）的新型抑制剂；（3）探索与PI3K或MAPK等其他关键通路抑制剂的新型联合疗法。对晚期前列腺癌进行更深入的基因组亚型分析，将有助于识别最可能从细胞周期靶向药物中获益的患者亚群。
Cyclin-Dependent Kinase Inhibition in Prostate Cancer: Past, Present, and Future
肿瘤(癌症)患者之家