Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth.
Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth.
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DOI：
10.1158/1535-7163.mct-16-0197
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发表时间：
2016-09
影响因子：
5.7
通讯作者：
Weiss RH
中科院分区：
文献类型：
--
作者：
Abu Aboud O;Chen CH;Senapedis W;Baloglu E;Argueta C;Weiss RH
肾癌（或肾细胞癌，RCC）是美国第六大常见恶性肿瘤，也是发病率不断上升的少数几种恶性肿瘤之一。由于使用目前的治疗方案几乎普遍存在耐药性，因此正在研究重编程代谢途径作为这种疾病新疗法的潜在靶点。借鉴对其他恶性肿瘤的研究，我们已经确定PAK 4和NAD生物合成途径对RCC生长至关重要。我们现在表明，使用双重PAK 4/NAMPT抑制剂KPT-9274，干扰这些信号通路导致G2/M期转运减少，以及诱导细胞凋亡和细胞侵袭和迁移减少在几个人RCC细胞系。机制研究表明，KPT-9274对PAK 4通路的抑制减弱了核β-catenin以及Wnt/β-catenin靶向细胞周期蛋白D1和c-Myc。此外，我们显示在所有测试的RCC细胞系中发生的NAPRT 1下调使得该肿瘤高度依赖于NAMPT以满足其NAD需求，使得KPT-9274对NAMPT的抑制导致这些快速增殖细胞的存活率降低。当将KPT-9274体内给予786-O（VHL-mut）人RCC异种移植模型时，对肿瘤生长有剂量依赖性抑制作用，无明显毒性; KPT-9274在该小鼠模型中显示了预期的靶向作用。KPT-9274正在实体瘤和淋巴瘤的1期人体临床试验中进行评估，这将使这些数据能够迅速转化为临床RCC治疗。
Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the US and one of the relatively few whose incidence is increasing. Due to the near universal resistance which occurs with the use of current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies of this disease. Borrowing from studies on other malignancies, we have identified the PAK4 and NAD biosynthetic pathways as being essential for RCC growth. We now show, using the dual PAK4/NAMPT inhibitor KPT-9274, that interference with these signaling pathways results in reduction of G2/M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. Furthermore, NAPRT1 downregulation which we show occurs in all RCC cell lines tested makes this tumor highly dependent on NAMPT for its NAD requirements, such that inhibition of NAMPT by KPT-9274 leads to decreased survival of these rapidly proliferating cells. When KPT-9274 was administered in vivo to a 786-O (VHL-mut) human RCC xenograft model, there was dose-dependent inhibition of tumor growth with no apparent toxicity; KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 is being evaluated in a phase 1 human clinical trial in solid tumors and lymphomas which will allow this data to be rapidly translated into the clinic for the treatment of RCC.