Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer.
Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer.
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DOI：
10.1158/0008-5472.can-17-1494
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发表时间：
2018-02-01
期刊：
影响因子：
11.2
通讯作者：
Keyomarsi K
中科院分区：
文献类型：
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作者：
Carey JPW;Karakas C;Bui T;Chen X;Vijayaraghavan S;Zhao Y;Wang J;Mikule K;Litton JK;Hunt KK;Keyomarsi K
PARP 抑制剂 (PARPi) 仅使一小部分乳腺癌患者受益。其中一些患者表现出内在/获得性耐药机制，限制了 PARPi 单一疗法的疗效。在这里，我们展示了如何通过靶向 MYC 诱导的致癌成瘾来扩大 PARPi 在三阴性乳腺癌 (TNBC) 中的疗效。在 BRCA 突变/散发性 TNBC 患者中，MYC 基因的扩增与同源 DNA 重组酶 RAD51 的表达增加相关，而过度表达这两种基因的肿瘤与较差的总体生存率相关。将 MYC 阻断与 PARPi 相结合，可以在 MYC 驱动的 TNBC 细胞中产生合成致死作用。使用下调 MYC 表达的细胞周期蛋白依赖性激酶抑制剂 dinaciclib，我们发现与 PARPi niraparib 组合会增加 DNA 损伤并下调同源重组，导致随后上皮间质转化 (EMT) 和癌症干细胞样细胞表型的下调。值得注意的是，dinaciclib 使已经对 niraparib 产生耐药性的 TBNC 细胞重新敏感。我们发现使用 dinaciclib 和 niraparib 的合成致死策略对卵巢癌、前列腺癌、胰腺癌、结肠癌和肺癌细胞也非常有效。总而言之，我们的结果表明，减弱 MYC 癌基因成瘾性可以如何利用癌细胞对 PARPi 的敏感性，从而促进 c-myc 作为这种治疗的预测生物标志物的临床使用。
PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial-mesenchymal transition (EMT) and cancer stem-like cell phenotypes. Notably, dinaciclib re-sensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.