Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment
Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment
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DOI：
10.4161/cc.22026
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发表时间：
2012-10-15
期刊：
影响因子：
4.3
通讯作者：
Bartek, Jiri
中科院分区：
文献类型：
--
作者：
Oplustilova, Lenka;Wolanin, Kamila;Bartek, Jiri
受损的DNA损伤反应途径可能会造成癌细胞的脆弱性，可以在治疗上加以利用。其中一种选择性的脆弱性是BRCA 1或BRCA 2缺陷肿瘤的敏感性（因此在通过同源重组的DNA修复中有缺陷，HR）对多聚腺苷酸的抑制剂（ADP-核糖）聚合酶-1（PARP-1），一种对HR替代修复途径至关重要的酶。虽然有希望，但用PARP-1抑制剂（PARP-1 i）治疗面临一些障碍，包括（1）获得性耐药性，（2）寻找其他致敏的非BRCA 1/2癌症缺陷和（3）缺乏生物标志物来预测对PARP-1 i的反应。在这里，我们使用PARP-1 i对来自乳腺癌、前列腺癌、结肠癌、胰腺癌和卵巢癌的20种人类细胞系进行了研究。Mre 11-Rad 50-Nbs 1（MRN）复合物的畸变使癌细胞对PARP-1 i敏感，而p53状态的预测性较低，即使对PARP-1 i与喜树碱或电离辐射的组合也是如此。此外，监测PAR基化和Rad 51病灶形成分别作为PARP活性和HR的替代标志物，支持其作为PARP-1 i反应生物标志物的候选资格。至于耐药机制，我们证实了多药耐药外排转运蛋白的作用及其可逆性。更重要的是，我们证明了shRNA慢病毒介导的人BRCA 1突变乳腺癌细胞中53 BP 1的耗竭增加了它们对PARP-1 i的抗性。鉴于BRCA缺陷和三阴性乳腺癌中53 BP 1的优先丢失，我们的研究结果证明了53 BP 1在PARPi反应的候选预测生物标志物中的评估。总的来说，这项研究有助于表征对PARP-1 i的细胞反应的遗传和功能决定因素，并有助于寻找生物标志物以利用PARP抑制剂进行癌症治疗。
Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly(ADP-ribose) polymerase- 1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i combinations with camptothecin or ionizing radiation. Furthermore, monitoring PARsylation and Rad51 foci formation as surrogate markers for PARP activity and HR, respectively, supported their candidacy for biomarkers of PARP-1i responses. As to resistance mechanisms, we confirmed the role of the multidrug resistance efflux transporters and its reversibility. More importantly, we demonstrated that shRNA lentivirus-mediated depletion of 53BP1 in human BRCA1- mutant breast cancer cells increased their resistance to PARP-1i. Given the preferential loss of 53BP1 in BRCA-defective and triple-negative breast carcinomas, our findings warrant assessment of 53BP1 among candidate predictive biomarkers of response to PARPi. Overall, this study helps characterize genetic and functional determinants of cellular responses to PARP-1i and contributes to the search for biomarkers to exploit PARP inhibitors in cancer therapy.