PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas.
PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas.
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DOI：
10.18632/oncotarget.12270
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发表时间：
2016-11-15
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影响因子：
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通讯作者：
Skorski T
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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
包括黑色素瘤在内的癌症可能对双链断裂（DSB）修复“上瘾”，靶向这一过程可能会使它们对DNA损伤的致命影响敏感。PARP1对DSB修复有重要影响，因为它可以结合单链和双链断裂。PARP1抑制剂可能是在DNA修复基因中存在种系或体细胞缺陷的肿瘤患者中引发合成致死的高效药物。我们假设，在显示DSB修复基因下调的黑色素瘤细胞中，parp1依赖性的合成致死性可能被诱导。我们观察到PARP1抑制剂奥拉帕尼在体外使DNA连接酶4 （LIG4）表达降低的黑色素瘤对烷基化剂达卡巴嗪（DTIC）敏感，而正常黑色素细胞保持完整。PARP1抑制引起dsb的积累，这与LIG4缺陷黑色素瘤细胞的凋亡有关。我们的假设是，奥拉帕尼对LIG4缺乏的黑色素瘤细胞具有合成致死性，这一假设得到了奥拉帕尼单独使用或与达卡巴嗪（DTIC）联合使用对LIG4缺乏而不是LIG4精通的细胞具有选择性抗肿瘤作用的支持。此外，奥拉帕尼联合DTIC抑制了LIG4缺陷的人黑色素瘤异种移植物的生长。这项工作首次证明了PARP1抑制剂奥拉帕尼和烷基化剂DTIC联合治疗LIG4缺陷黑色素瘤的有效性。此外，对TCGA和转录组微阵列数据库的分析显示，许多黑色素瘤个体样本可能在DSB修复途径中显示特定缺陷，这可能使它们易于由PARP1抑制剂联合细胞毒性药物引发的合成致死。
Cancer including melanoma may be “addicted” to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug.