6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance.
6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance.
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DOI：
10.1158/0008-5472.can-09-3416
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发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Helleday T
中科院分区：
文献类型：
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作者：
Issaeva N;Thomas HD;Djureinovic T;Jaspers JE;Stoimenov I;Kyle S;Pedley N;Gottipati P;Zur R;Sleeth K;Chatzakos V;Mulligan EA;Lundin C;Gubanova E;Kersbergen A;Harris AL;Sharma RA;Rottenberg S;Curtin NJ;Helleday T
家族性乳腺癌和卵巢癌通常由于BRCA 1或BRCA 2基因突变而导致同源重组（HR）缺陷。顺铂化疗或聚（ADP-核糖）聚合酶（PARP）抑制剂在临床试验中测试这些肿瘤。在筛选选择性杀死BRCA 2缺陷细胞的新药时，我们鉴定了6-硫代鸟嘌呤（6 TG），它诱导DNA双链断裂（DSB），我们发现这些断裂是由HR. Further修复的，我们发现6 TG在异种移植模型中选择性杀死BRCA 2缺陷肿瘤方面与PARP抑制剂一样有效。自发性BRCA 1缺陷型乳腺肿瘤通过增加p-糖蛋白表达获得对PARP抑制剂的耐药性。在这里，我们表明6 TG有效地杀死这种BRCA 1缺陷型PARP抑制剂耐药（PIR）肿瘤。我们还表明，6 TG可以杀死通过BRCA 2基因的遗传逆转而对PARP抑制剂或顺铂产生耐药性的细胞和肿瘤。虽然HR在PIR BRCA 2缺陷细胞中被重新激活，但对于6 TG诱导的损伤的修复，它并没有完全恢复。这可能是由于6 TG后形成的几个重组性病变。我们发现BRCA 2是生存所必需的，也是由6 TG形成的不包括DSB的不匹配修复的病变所必需的。这表明HR参与6 TG诱导的DSB的修复以及不依赖于错配修复的6 TG诱导的DNA损伤。总之，我们的数据表明，6 TG有效地杀死BRCA 2缺陷型肿瘤，并表明6 TG可能有效地治疗对PARP抑制剂或铂类化疗产生耐药性的晚期肿瘤。
Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors are tested for these tumours in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSBs) that we show are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumours in a xenograft model. Spontaneous BRCA1 defective mammary tumours gain resistance to PARP inhibitors through increased p-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1 defective PARP inhibitor resistant (PIR) tumours. We also show that 6TG can kill cells and tumours that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PIR BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is required for survival also to mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumours and suggest that 6TG may be effective in the treatment of advanced tumours that have developed resistance to PARP inhibitors or platinum-based chemotherapy.