PO.ET03.03 · 实验与分子治疗
在晚期前列腺癌中用临床阶段ATM抑制剂靶向PARPi药物耐受持续性及治疗中进展
Targeting PARPi drug tolerant persistence and progression on treatment with clinical stage ATM inhibitors in advanced prostate cancer
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PARP抑制剂（PARPi）改善了前列腺癌的管理，但进展不可避免。药物耐受持续性（DTP）的特征是肿瘤细胞在治疗中存活，并通过短暂获得不敏感性驱动治疗失败。周期性DTP细胞可能适应并扩增，产生药物耐受扩增持续细胞（DTEP）群体，被认为可模拟治疗中进展。新出现的证据支持DTP在促进PARPi进展中的关键作用。识别并靶向DTP和DTEP的脆弱性可能提供对抗疾病进展的治疗策略。
方法：活力测定、Western blot及其他测定确定PARPi敏感的C4-2B转移性去势抵抗性前列腺癌细胞及其阿比特龙耐药衍生细胞AbiR的治疗反应。通过长期PARPi暴露建立DTP和DTEP模型。NGS对DTP细胞进行分析。测试临床阶段ATM抑制剂对DTP和DTEP群体的影响。
结果：对PARP抑制的反应具有异质性，其特征为细胞死亡及一个主要为静止的持续群体的出现。C4-2B和AbiR细胞暴露于临床相关PARPi给药9天，随后药物假期，可恢复正常的亲本细胞形态并对治疗重新敏感，与获得DTP表型一致。DTP细胞较亲本细胞对其他类别药物表现出不同的敏感性。DTP细胞可大致分为两类：1）少数进行周期循环者，2）不进行者。观察到长期PARPi治疗导致源自周期性DTP细胞的药物耐受扩增持续细胞（DTEP）。DTP和DTEP细胞显示磷酸化ATM水平升高，提示组成型DNA损伤反应激活。利用临床阶段ATM抑制剂既可阻止DTP进展为DTEP，又可使DTEP对PARP抑制重新敏感。
结论：我们的数据提示，药物耐受持续性可能介导驱动治疗中进展的肿瘤细胞存活。ATM抑制可用于延长至进展的时间或治疗进展性疾病。未来研究将聚焦于转化这些策略。
查看英文原文 English abstract
Background: PARP inhibitors (PARPi) have improved prostate cancer management, but progression is inevitable. Drug tolerant persistence (DTP) is characterized by tumor cells which survive treatment and drive failure through transient acquisition of insensitivity. Cycling DTP cells may adapt and expand, giving rise to drug tolerant expanded persister (DTEP) populations which are thought to model progression on treatment. Emerging evidence supports a critical role for DTP in promoting PARPi progression. Identifying and targeting DTP and DTEP vulnerabilities may provide therapeutic strategies to combat disease progression.
Methods: Viability assays, western blots, and additional assays defined treatment response in PARPi-sensitive C4-2B metastatic castration-resistant prostate cancer cells and C4-2B abiraterone-resistant derivative AbiR cells. DTP and DTEP models were developed through prolonged PARPi exposure. NGS profiled DTP cells. Clinical stage ATM inhibitors were tested for their effects on both DTP and DTEP populations.
Results: Response to PARP inhibition is heterogeneous, characterized by cell death and emergence of a largely cytostatic, persistent population. C4-2B and AbiR cells exposed to clinically relevant PARPi dosing for 9 days followed by drug holiday regain normal, parental cell morphology and become re-sensitized to treatment in line with acquisition of a DTP phenotype. DTP cells display differential sensitivity to other classes of drugs compared to parental cells. DTP cells may be broadly stratified into two classes; 1) a minority which cycle and 2) those which don't. Prolonged PARPi treatment is observed to result in drug tolerant expanded persisters (DTEP) derived from cycling-DTP cells. DTP and DTEP cells display increased phospho-ATM levels suggesting constitutive DNA damage response activation. Utilization of clinical stage ATM inhibitors both prevent DTP progression into DTEPs and resensitize DTEPs to PARP inhibition.
Conclusions: Our data suggest that drug tolerant persistence may mediate survival of tumor cells which drive progression on treatment. ATM inhibition may be used to prolong time to progression or to treat progressive disease. Future studies will focus on translating these strategies.
利益披露 Disclosure
A. Karthikeyan, None..
B. Correa Gonzalez, None..
J. G. Torres-Gonzalez, None..
L. A. Moore, None..
A. Bhaumik, None..
E. Sandoval, None.
A. P. Lombard,
FGH Biotech Independent Contractor.