PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models.
PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models.
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DOI：
10.1186/s12943-017-0652-5
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发表时间：
2017-04-28
期刊：
影响因子：
37.3
通讯作者：
Grignani G
中科院分区：
文献类型：
--
作者：
Pignochino Y;Capozzi F;D'Ambrosio L;Dell'Aglio C;Basiricò M;Canta M;Lorenzato A;Vignolo Lutati F;Aliberti S;Palesandro E;Boccone P;Galizia D;Miano S;Chiabotto G;Napione L;Gammaitoni L;Sangiolo D;Benassi MS;Pasini B;Chiorino G;Aglietta M;Grignani G
增强DNA损伤药物的抗肿瘤活性是改善当前治疗选择的有吸引力的策略。Trabectedin是一种具有独特作用机制的异喹啉烷化剂。它与DNA小沟结合，诱导单链和双链断裂。这些类型的损伤导致PARP 1的激活，PARP 1是DNA损伤反应途径中的一线酶。我们假设PARP 1靶向可以使trabectedin诱导的肿瘤细胞DNA损伤永久化，最终导致细胞死亡。我们在体外和体内（小鼠皮下和原位肿瘤异种移植物）研究了trabectedin和PARP 1抑制剂在几种肿瘤组织型中的协同作用。我们通过比较基因组杂交（aCGH）和基因表达谱（GEP）寻找药物协同作用的关键决定因素，并验证其功能作用。如果与单一药物相比，曲贝替定激活PARP 1酶，并且与PARP 1抑制剂组合增强DNA损伤、G2/M检查点的细胞周期阻滞和细胞凋亡。奥拉帕尼是与曲贝替丁联合收割机最有效的PARP 1抑制剂，我们在小鼠模型中证实了曲贝替丁/奥拉帕尼组合的抗肿瘤和抗转移活性。然而，我们在不同的细胞系中观察到不同程度的曲贝替丁/奥拉帕尼协同作用。也就是说，在DMR平滑肌肉瘤模型中，组合比单一药剂显著更有活性，而在SJSA-1骨肉瘤模型中，如果与单独的曲贝替丁相比，则没有获得进一步的优势。aCGH和GEP揭示了DNA修复途径的关键组分参与了曲贝替丁/奥拉帕尼的协同作用。特别是，PARP 1表达决定了协同作用的程度。事实上，在PARP 1过表达后，trabectedin/olaparib协同作用增加，而在PARP 1沉默后，协同作用减少。PARP 1抑制以PARP 1依赖的方式增强trabectedin活性，并且PARP 1在肿瘤细胞中的表达可能是值得临床评价的有用的预测生物标志物。本文的在线版本（doi：10.1186/s12943-017-0652-5）包含补充材料，可供授权用户使用。
Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death. We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing. PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation. The online version of this article (doi:10.1186/s12943-017-0652-5) contains supplementary material, which is available to authorized users.