Pre-Existing and Acquired Resistance to PARP Inhibitor-Induced Synthetic Lethality.
Pre-Existing and Acquired Resistance to PARP Inhibitor-Induced Synthetic Lethality.
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作者：
PARP抑制剂（PARPi）已被用于治疗BRCA 1/2突变/缺陷型恶性肿瘤。然而，对PARPi的耐药性正在实验和临床干预中出现。重要的是，耐药性源于不同的机制，因此需要付出巨大的努力来确定机制方面并开发联合疗法以防止耐药性和/或恢复PARPi在癌细胞中的效率。在这里，我们回顾了对PARPi的既存和获得性耐药性，并提出了潜在的治疗方案。合成杀伤力的先进发展为个性化医疗和有效治疗癌症的特定抗癌药物打开了大门。正在研究的最受欢迎的方法之一是靶向DNA修复途径，将PARP抑制剂（PARPi）应用到单独或组合治疗方案中。这种治疗已经有效地用于对抗同源重组缺陷型实体瘤以及造血系统恶性肿瘤。然而，在临床前研究和临床治疗中均观察到对PARPi的耐药性。因此，阐明对PARPi产生抗性的机制对于这种干预的进一步成功至关重要。除了获得性抗性的机制之外，骨髓微环境提供了诱导PARPi在白血病细胞中无效的预先存在的机制。在这里，我们描述了预先存在的和获得的机制的阻力PARPi诱导的合成致死。我们还讨论了开发有效疗法以预防/抑制癌细胞中PARPi抗性的潜在原理。
PARP inhibitors (PARPi) have been administered to treat BRCA1/2-mutated/deficient malignancies. Nevertheless, the resistance to PARPi is emerging in experimental and clinical interventions. Importantly, the resistance originated from diverse mechanisms, therefore requiring tremendous efforts to identify mechanistic aspects and develop combinational therapies to prevent the resistance and/or restore the efficiency of PARPi in cancer cells. Here, we review pre-existing and acquired resistance to PARPi and propose potential therapeutic solutions. The advanced development of synthetic lethality has opened the doors for specific anti-cancer medications of personalized medicine and efficient therapies against cancers. One of the most popular approaches being investigated is targeting DNA repair pathways as the implementation of the PARP inhibitor (PARPi) into individual or combinational therapeutic schemes. Such treatment has been effectively employed against homologous recombination-defective solid tumors as well as hematopoietic malignancies. However, the resistance to PARPi has been observed in both preclinical research and clinical treatment. Therefore, elucidating the mechanisms responsible for the resistance to PARPi is pivotal for the further success of this intervention. Apart from mechanisms of acquired resistance, the bone marrow microenvironment provides a pre-existing mechanism to induce the inefficiency of PARPi in leukemic cells. Here, we describe the pre-existing and acquired mechanisms of the resistance to PARPi-induced synthetic lethality. We also discuss the potential rationales for developing effective therapies to prevent/repress the PARPi resistance in cancer cells.
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影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
--
作者：
Czyż M;Toma M;Gajos-Michniewicz A;Majchrzak K;Hoser G;Szemraj J;Nieborowska-Skorska M;Cheng P;Gritsyuk D;Levesque M;Dummer R;Sliwinski T;Skorski T
通讯作者：
Skorski T
DOI：
10.1073/pnas.0915067107
发表时间：
2010-02-16
影响因子：
11.1
作者：
Boboila, Cristian;Jankovic, Mila;Alt, Frederick W.
通讯作者：
Alt, Frederick W.
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
影响因子：
28.2
作者：
de Bono J;Ramanathan RK;Mina L;Chugh R;Glaspy J;Rafii S;Kaye S;Sachdev J;Heymach J;Smith DC;Henshaw JW;Herriott A;Patterson M;Curtin NJ;Byers LA;Wainberg ZA
通讯作者：
Wainberg ZA