Jang Albert, Sartor Oliver, Barata Pedro C, Paller Channing J
Deming Department of Medicine, Hematology-Oncology Section, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Tulane Cancer Center, New Orleans, LA 70112, USA.
Cancers (Basel). 2020 Nov 21;12(11):3467. doi: 10.3390/cancers12113467.
Metastatic castration-resistant prostate cancer (mCRPC) is an incurable malignancy with a poor prognosis. Up to 30% of patients with mCRPC have mutations in homologous recombination repair (HRR) genes. Poly (ADP-ribose) polymerase (PARP) inhibitors take advantage of HRR deficiency to kill tumor cells based on the concept of synthetic lethality. Several PARP inhibitors (PARPis) have been successful in various malignancies with HRR gene mutations including BRCA1/2, especially in breast cancer and ovarian cancer. More recently, olaparib and rucaparib were approved for mCRPC refractory to novel hormonal therapies, and other PARPis will likely follow. This article highlights the mechanism of action of PARPis at the cellular level, the preclinical data regarding a proposed mechanism of action and the effectiveness of PARPis in cancer cell lines and animal models. The article expands on the clinical development of PARPis in mCRPC, discusses potential biomarkers that may predict successful tumor control, and summarizes present and future clinical research on PARPis in the metastatic disease landscape.
转移性去势抵抗性前列腺癌（mCRPC）是一种无法治愈的恶性肿瘤，预后较差。高达30%的mCRPC患者在同源重组修复（HRR）基因中存在突变。聚（ADP-核糖）聚合酶（PARP）抑制剂基于合成致死的概念，利用HRR缺陷来杀死肿瘤细胞。几种PARP抑制剂（PARPis）已在包括BRCA1/2在内的多种具有HRR基因突变的恶性肿瘤中取得成功，尤其是在乳腺癌和卵巢癌中。最近，奥拉帕利和卢卡帕利被批准用于对新型激素疗法难治的mCRPC，其他PARPis可能也会相继获批。本文重点介绍了PARPis在细胞水平的作用机制、关于其拟议作用机制的临床前数据以及PARPis在癌细胞系和动物模型中的有效性。本文还阐述了PARPis在mCRPC中的临床开发情况，讨论了可能预测肿瘤控制成功的潜在生物标志物，并总结了在转移性疾病领域中PARPis目前和未来的临床研究。
