Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges.
Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges.
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DOI：
10.1200/po.21.00211
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发表时间：
2022-03
影响因子：
4.6
通讯作者：
Chen JL
中科院分区：
文献类型：
--
作者：
Hsu JY;Seligson ND;Hays JL;Miles WO;Chen JL
软组织肉瘤和骨肉瘤是一种罕见的恶性肿瘤，表现出明显的病理和分子异质性。CDKN2A-CCND-CDK4/6-视网膜母细胞瘤1(RB)通路的失控常见于约25%的非选择性肉瘤，并与特定的肉瘤亚型有关。这种基因组特异性推动了选择性CDK4/6抑制剂在肉瘤中的临床评估。在这里，我们重点介绍使用CDK4/6抑制剂治疗肉瘤的成功、机遇和未来的挑战。本文总结了CDK4/6抑制剂在肉瘤中应用的最新证据，同时确定了分子基础和预测生物标志物，为在肉瘤中靶向CDK4/6通路提供了基础。对PubMed数据库和美国国立卫生研究院临床试验注册中心(ClinicalTrials.gov)索引的文章进行了系统的审查。对于每一种肉瘤亚型，我们讨论了临床前的理论基础、病例报告和可用的临床试验数据。尽管在肉瘤的一个亚组中有很好的临床结果，但对CDK4/6抑制剂的耐药性导致高度不同的临床结果。目前的临床数据支持CDK4/6抑制剂在肉瘤亚群中的使用，这些亚群主要是由CDK4/6去调控驱动的。当Rb通路的失调是肉瘤的第二驱动因素时，联合抑制CDK4/6可能是一种选择。制定策略以确定应答者和驱动耐药性的机制，对于最大限度地发挥这些药物在肉瘤患者中的临床效用非常重要。提示CDK4/6抑制剂在肉瘤中敏感性的潜在生物标志物包括CDK4、CCND、CCNE、RB1、E2F1和CDKN2A。CDK4/6抑制剂是肿瘤靶向治疗的重大突破。CDK4/6抑制剂在肉瘤中的应用导致了有限但意义重大的早期临床成功。未来有针对性的临床研究将是释放CDK4/6抑制在肉瘤中的潜力的关键。
Soft tissue and bone sarcomas are rare malignancies that exhibit significant pathologic and molecular heterogeneity. Deregulation of the CDKN2A-CCND-CDK4/6-retinoblastoma 1 (Rb) pathway is frequently observed in about 25% of unselected sarcomas and is pathognomonic for specific sarcoma subtypes. This genomic specificity has fueled the clinical evaluation of selective CDK4/6 inhibitors in sarcomas. Here, we highlight successes, opportunities, and future challenges for using CDK4/6 inhibitors to treat sarcoma. This review summarizes the current evidence for the use of CDK4/6 inhibitors in sarcoma while identifying molecular rationale and predictive biomarkers that provide the foundation for targeting the CDK4/6 pathway in sarcoma. A systematic review was performed of articles indexed in the PubMed database and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov). For each sarcoma subtype, we discuss the preclinical rationale, case reports, and available clinical trials data. Despite promising clinical outcomes in a subset of sarcomas, resistance to CDK4/6 inhibitors results in highly heterogeneous clinical outcomes. Current clinical data support the use of CDK4/6 inhibitors in subsets of sarcoma primarily driven by CDK4/6 deregulation. When dysregulation of the Rb pathway is a secondary driver of sarcoma, combination therapy with CDK4/6 inhibition may be an option. Developing strategies to identify responders and the mechanisms that drive resistance is important to maximize the clinical utility of these drugs in patients with sarcoma. Potential biomarkers that indicate CDK4/6 inhibitor sensitivity in sarcoma include CDK4, CCND, CCNE, RB1, E2F1, and CDKN2A. CDK4/6 inhibitors represent a major breakthrough for targeted cancer treatment. CDK4/6 inhibitor use in sarcoma has led to limited, but significant, early clinical success. Targeted future clinical research will be key to unlocking the potential of CDK4/6 inhibition in sarcoma.