The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
EMBO Mol Med. 2012 Oct;4(10):1087-96. doi: 10.1002/emmm.201201250. Epub 2012 Aug 30.
PARP inhibitors have been proposed as a potential targeted therapy for patients with triple-negative (ER-, PR-, HER2-negative) breast cancers. However, it is as yet unclear as to whether single agent or combination therapy using PARP inhibitors would be most beneficial. To better understand the mechanisms that determine the response to PARP inhibitors, we investigated whether enzymes involved in metabolism of the PARP substrate, β-NAD(+) , might alter the response to a clinical PARP inhibitor. Using an olaparib sensitization screen in a triple-negative (TN) breast cancer model, we identified nicotinamide phosphoribosyltransferase (NAMPT) as a non-redundant modifier of olaparib response. NAMPT is a rate-limiting enzyme involved in the generation of the PARP substrate β-NAD(+) and the suppression of β-NAD(+) levels by NAMPT inhibition most likely explains these observations. Importantly, the combination of a NAMPT small molecule inhibitor, FK866, with olaparib inhibited TN breast tumour growth in vivo to a greater extent than either single agent alone suggesting that assessing NAMPT/PARP inhibitor combinations for the treatment of TN breast cancer may be warranted.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂被提议作为三阴性（雌激素受体[ER]-、孕激素受体[PR]-、人表皮生长因子受体 2[HER2]-阴性）乳腺癌患者的一种潜在靶向治疗方法。然而，目前尚不清楚使用 PARP 抑制剂的单一药物治疗还是联合治疗将最有益。为了更好地了解决定 PARP 抑制剂反应的机制，我们研究了参与 PARP 底物 β-NAD（+）代谢的酶是否可能改变对临床 PARP 抑制剂的反应。我们在三阴性（TN）乳腺癌模型中使用奥拉帕利增敏筛选，鉴定烟酰胺磷酸核糖转移酶（NAMPT）是奥拉帕利反应的非冗余调节剂。NAMPT 是一种限速酶，参与 PARP 底物 β-NAD（+）的生成，NAMPT 抑制降低 β-NAD（+）水平，这很可能解释了这些观察结果。重要的是，NAMPT 小分子抑制剂 FK866 与奥拉帕利的联合使用在体内更能抑制 TN 乳腺癌肿瘤生长，比单独使用任一药物的效果都要好，这表明评估 NAMPT/PARP 抑制剂联合治疗 TN 乳腺癌可能是合理的。
