卵巢和子宫癌肉瘤中的同源重组缺陷 (HRD) 特征 3 与奥拉帕利（一种多聚（腺苷二磷酸 [ADP]-核糖）聚合酶 (PARP) 抑制剂）的临床前敏感性相关。
Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to Olaparib, a poly (adenosine diphosphate [ADP]- ribose) polymerase (PARP) inhibitor.
机构信息
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Department of Biomedical Sciences, Korea University College of Medicine, 02841 Seoul, Republic of Korea; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, United States of America.
出版信息
Gynecol Oncol. 2022 Jul;166(1):117-125. doi: 10.1016/j.ygyno.2022.05.005. Epub 2022 May 20.
OBJECTIVES
Carcinosarcoma (CS) of the ovary and uterus are highly aggressive malignancies associated with poor survival. Poly(ADP-ribose)-polymerase inhibitors (PARPi) are targeted agents impairing DNA repair via homologous-recombination-deficiency (HRD) mechanisms. We used whole-exome-sequencing (WES) data from a cohort of fresh tumor samples of ovarian (OCS) and uterine carcinosarcoma (UCS), primary cell lines and xenografts to investigate the role for olaparib in CSs.
METHODS
WES data from 73 CS samples (48 UCS and 25 OCS) were analyzed for HRD signatures. Olaparib activity was evaluated using cell-viability, cell-cycle, apoptosis and cytotoxicity assays against primary CS cell lines. Olaparib antitumor activity was tested in vivo against HRD CS xenografts.
RESULTS
Signature-3 (i.e. HRD-related signature) was identified in 60% of OCS (15 of 25) vs 25% of UCS (12 of 48) (p = 0.005). CS cell lines harboring Signature-3/HRD (3 OCS/1 UCS) were significantly more sensitive to olaparib when compared to HRP cell lines (5 UCS/1 OCS) [mean IC ± SEM = 2.94 μM ± 0.07 vs mean ± SEM = 23.3 μM ± 0.09, (p = 0.02), respectively]. PARPi suppressed CS cell growth through cell cycle arrest in the G2/M phase and caused more apoptosis in HRD vs HRP primary tumors (p < 0.0001). In vivo, olaparib significantly impaired HRD CS xenografts tumor growth (p = 0.0008) and increased overall animal survival (p < 0.0001).
CONCLUSIONS
OCS and UCS cell lines harboring HRD signature-3 were significantly more sensitive to olaparib in vitro and in vivo when compared to HRP CS. Clinical studies with PARPi in CS patients with a dominant signature 3 (HRD-related) are warranted.
目的
卵巢和子宫的癌肉瘤（CS）是高度侵袭性的恶性肿瘤，生存预后较差。聚（ADP-核糖）-聚（ADP-核糖）聚合酶抑制剂（PARPi）是通过同源重组缺陷（HRD）机制破坏 DNA 修复的靶向药物。我们使用卵巢（OCS）和子宫癌肉瘤（UCS）新鲜肿瘤样本的全外显子组测序（WES）数据，对一组卵巢和子宫癌肉瘤的原发性细胞系和异种移植瘤进行分析，以研究奥拉帕利在 CS 中的作用。
方法
对 73 例 CS 样本（48 例 UCS 和 25 例 OCS）的 WES 数据进行 HRD 特征分析。利用细胞活力、细胞周期、凋亡和细胞毒性测定法，对原发性 CS 细胞系进行奥拉帕利活性评估。针对 HRD CS 异种移植瘤，在体内进行奥拉帕利抗肿瘤活性测试。
结果
在 25 例 OCS 中有 60%（15 例），而在 48 例 UCS 中有 25%（12 例）存在 Signature-3（即 HRD 相关特征）（p=0.005）。与 HRP 细胞系相比，携带 Signature-3/HRD（3 例 OCS/1 例 UCS）的 CS 细胞系对奥拉帕利的敏感性显著更高[平均 IC ± SEM=2.94μM±0.07 对平均 ± SEM=23.3μM±0.09，（p=0.02）]。PARPi 通过将 CS 细胞周期阻滞在 G2/M 期而抑制 CS 细胞生长，并在 HRD 与 HRP 原发性肿瘤中引起更多的细胞凋亡（p＜0.0001）。在体内，奥拉帕利显著抑制 HRD CS 异种移植瘤的肿瘤生长（p=0.0008）并增加动物的总生存（p＜0.0001）。
结论
与 HRP CS 相比，携带 HRD Signature-3 的 OCS 和 UCS 细胞系在体外和体内对奥拉帕利的敏感性显著更高。在具有主导 Signature 3（HRD 相关）的 CS 患者中进行 PARPi 的临床研究是必要的。
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