Olaparib-Induced Senescence Is Bypassed through G2-M Checkpoint Override in Olaparib-Resistant Prostate Cancer.
Olaparib-Induced Senescence Is Bypassed through G2-M Checkpoint Override in Olaparib-Resistant Prostate Cancer.
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DOI：
10.1158/1535-7163.mct-21-0604
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发表时间：
2022-04-01
影响因子：
5.7
通讯作者：
Gao AC
中科院分区：
文献类型：
--
作者：
Lombard AP;Armstrong CM;D'Abronzo LS;Ning S;Leslie AR;Sharifi M;Lou W;Evans CP;Dall'Era M;Chen HW;Chen X;Gao AC
PARP 抑制代表了治疗前列腺癌的精准医学的曙光。尽管取得了这一进展，但关于使用 PARP 抑制剂 (PARPi) 治疗这种疾病仍存在疑问，包括 1) PARPi 敏感肿瘤细胞对治疗的具体反应如何，以及 2) PARPi 耐药性如何发展？为了解决这些问题，我们表征了敏感 LNCaP 和 C4-2B 细胞对奥拉帕尼的反应，并开发了两种奥拉帕尼耐药衍生细胞系模型，分别称为 LN-OlapR 和 2B-OlapR。 OlapR 细胞具有与亲代细胞不同的形态，并对 olaparib 和其他临床相关的 PARPi（包括 rucaparib、niraparib 和 talazoparib）表现出强大的耐药性。在 LNCaP 和 C4-2B 细胞中，我们发现奥拉帕尼诱导大量 DNA 损伤，导致 G2/M 检查点激活、p53 激活和细胞周期停滞。此外，我们的数据表明 G2/M 检查点激活会导致与 p21 活性相关的细胞死亡和衰老。相比之下，LN-OlapR 和 2B-OlapR 细胞均不会停滞在 G2/M 期，并且对奥拉帕尼治疗的反应明显减弱。有趣的是，与亲本细胞相比，两种 OlapR 细胞系都具有增加的 DNA 损伤，这表明 OlapR 细胞在获得抗性期间积累并管理持续的 DNA 损伤，可能是通过增强 DNA 修复能力。通过抑制 CDK1 进一步损害 DNA 修复会增强 DNA 损伤，诱导细胞死亡，并使 OlapR 细胞对奥拉帕尼治疗敏感。我们的数据进一步加深了我们对 PARPi 治疗的理解，并为研究 PARP 抑制的反应和耐药性提供了一个细胞平台系统。
PARP inhibition represents the dawn of precision medicine for treating prostate cancer. Despite this advance, questions remain regarding the use of PARP inhibitors (PARPi’s) for the treatment of this disease, including 1) how specifically do PARPi sensitive tumor cells respond to treatment, and 2) how does PARPi resistance develop? To address these questions, we characterized response to olaparib in sensitive LNCaP and C4–2B cells and developed two olaparib resistant derivative cell line models from each, termed LN-OlapR and 2B-OlapR respectively. OlapR cells possess distinct morphology from parental cells and display robust resistance to olaparib and other clinically relevant PARPi’s including rucaparib, niraparib, and talazoparib. In LNCaP and C4–2B cells, we found that olaparib induces massive DNA damage, leading to activation of the G2/M checkpoint, activation of p53, and cell cycle arrest. Furthermore, our data suggest that G2/M checkpoint activation leads to both cell death and senescence associated with p21 activity. In contrast, both LN-OlapR and 2B-OlapR cells do not arrest at G2/M and display a markedly blunted response to olaparib treatment. Interestingly, both OlapR cell lines harbor increased DNA damage relative to parental cells, suggesting that OlapR cells accumulate and manage persistent DNA damage during acquisition of resistance, likely through augmenting DNA repair capacity. Further impairing DNA repair through CDK1 inhibition enhances DNA damage, induces cell death, and sensitizes OlapR cells to olaparib treatment. Our data together further our understanding of PARPi treatment and provide a cellular platform system for the study of response and resistance to PARP inhibition.