A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.
A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.
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DOI：
10.1158/1535-7163.mct-15-0660
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发表时间：
2016-02
影响因子：
5.7
通讯作者：
Shmookler Reis RJ
中科院分区：
文献类型：
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作者：
Alagpulinsa DA;Ayyadevara S;Yaccoby S;Shmookler Reis RJ
聚（ADP-核糖）聚合酶1和2（PARP 1/2）是单链断裂修复所必需的，它们的抑制导致DNA复制叉塌陷和双链断裂（DSB）形成。这些DSB主要通过同源重组（HR）修复，这是一种高保真修复途径。如果HR是缺陷的，DSB可以通过易错的非同源末端连接机制修复，或者可以持续存在，最终导致细胞死亡。因此，在PARP和HR功能之间存在合成致死性。多发性骨髓瘤（MM）细胞的特征是染色体不稳定和广泛的DNA损伤，涉及异常的DNA修复。细胞周期蛋白依赖性激酶（CDK）是HR的上游调节剂，在MM中失调。在这里，我们表明CDK抑制剂dinaciclib会损害HR修复，并使MM细胞对PARP 1/2抑制剂ABT-888敏感。Dinaciclib可消除ABT-888诱导的BRCA 1和RAD 51病灶，并增强DNA损伤，表现为γ H2 AX病灶增加。Dinaciclib治疗降低HR修复基因（包括Rad 51）的表达，并阻断BRCA 1磷酸化（HR修复所需的修饰），从而抑制染色体DSB的HR修复。在体外，dinaciclib和ABT-888联合给药导致MM细胞的合成致死率，但对正常CD 19 + B细胞无影响，并使SCID小鼠中MM异种移植物的生长减慢近两倍。这些发现支持dinaciclib与PARP抑制剂联合治疗MM。
Poly(ADP-ribose) polymerases 1 and 2 (PARP1/2) are required for single-strand break repair, and their inhibition causes DNA replication-fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end joining mechanisms, or may persist, ultimately resulting in cell death. Synthetic lethality thus exists between PARP and HR functions. Multiple myeloma (MM) cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDKs), upstream modulators of HR, are dysregulated in MM. Here we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes MM cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased γH2AX foci. Dinaciclib treatment reduces expression of HR-repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosome DSBs. Co-treatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of MM cells, but not normal CD19+ B cells, and slowed growth of MM xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for MM therapy.