Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.
Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.
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DOI：
10.1038/nm.4032
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发表时间：
2016-02
期刊：
影响因子：
82.9
通讯作者：
Hung MC
中科院分区：
文献类型：
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作者：
Du Y;Yamaguchi H;Wei Y;Hsu JL;Wang HL;Hsu YH;Lin WC;Yu WH;Leonard PG;Lee GR 4th;Chen MK;Nakai K;Hsu MC;Chen CT;Sun Y;Wu Y;Chang WC;Huang WC;Liu CL;Chang YC;Chen CH;Park M;Jones P;Hortobagyi GN;Hung MC
在临床试验中，聚（ADP-核糖）聚合酶（PARP）抑制剂已成为治疗包括癌症在内的许多疾病的有前途的疗法。一种 PARP 抑制剂奥拉帕尼（Lynparza™，阿斯利康）最近被 FDA 批准用于治疗具有 BRCA 突变的卵巢癌。 BRCA1 和 BRCA2 在修复 DNA 双链断裂中发挥重要作用，BRCA 蛋白的缺乏会使癌细胞对 PARP 抑制敏感。在这里，我们证明受体酪氨酸激酶 c-Met 与 PARP1 Tyr907 结合并磷酸化。 PARP1 Tyr907 的磷酸化会增加 PARP1 酶活性并减少与 PARP 抑制剂的结合，从而使癌细胞对 PARP 抑制产生抵抗。 c-Met 和 PARP1 抑制剂相结合可协同抑制体外和异种移植肿瘤模型中乳腺癌细胞的生长。在肺癌异种移植肿瘤模型中观察到类似的协同效应。这些结果表明，PARP1 pTyr907 丰度可以预测肿瘤对 PARP 抑制剂的耐药性，并且 c-Met 和 PARP 抑制剂联合治疗可能有益于携带高 c-Met 表达的肿瘤的患者，这些患者对单独的 PARP 抑制没有反应。
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza™, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with BRCA mutations. BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone.