Inhibiting MDM2-p53 Interaction Suppresses Tumor Growth in Patient-Derived Non-Small Cell Lung Cancer Xenograft Models
Inhibiting MDM2-p53 Interaction Suppresses Tumor Growth in Patient-Derived Non-Small Cell Lung Cancer Xenograft Models
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DOI：
10.1097/jto.0000000000000584
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发表时间：
2015-08-01
影响因子：
20.4
通讯作者：
Tsao, Ming-Sound
中科院分区：
文献类型：
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作者：
Hai, Josephine;Sakashita, Shingo;Tsao, Ming-Sound
背景：抑癌基因P53在非小细胞肺癌(NSCLC)中经常失活。通过抑制负调控因子MDM2激活P53通路，可能为非小细胞肺癌的治疗提供一种有吸引力的途径。方法：采用一组人NSCLC细胞系(A549、H157、H1650、H1395和H358)和PDX细胞系(人肺细胞系12、137、277和196)，观察RG7388对细胞增殖、细胞周期停滞和细胞凋亡的影响。结果：RG7388选择性地促进野生型P53和P53途径激活的细胞株的低纳米分子抗增殖活性，导致细胞周期停滞和细胞凋亡。在PDX模型中，口服RG7388导致剂量依赖和时间依赖的P53激活，并对P53下游靶点有显著影响。在三种野生型p53 PDX模型中，RG7388每天分别以50 mg/kg和80 mg/kg的剂量治疗小鼠可抑制肿瘤生长。通过异种移植瘤中Ki-67阳性细胞的减少，观察到P53途径的激活抑制了细胞的增殖。然而，在这些肿瘤中没有观察到诱导凋亡的caspase活性。结论：MDM2小分子抑制剂治疗野生型P53阳性的非小细胞肺癌有效，为进一步的临床研究奠定了基础。
Background: The tumor suppressor p53 is frequently inactivated in non-small cell lung cancer (NSCLC). Activation of the p53 pathway by inhibition of its negative regulator MDM2 may offer an attractive approach for NSCLC therapy. We evaluated the antitumor activity of the small-molecule MDM2 inhibitor RG7388 in patient-derived xenograft (PDX) models of NSCLC.Methods: We investigated the effect of RG7388 treatment on cell proliferation, cell cycle arrest, and apoptosis using a panel of human NSCLC cell lines (A549, H157, H1650, H1395, and H358) and PDX cell lines (human lung cell lines 12, 137, 277, and 196). PDX-bearing mice were used to test the therapeutic efficacy and pharmacodynamic effects of RG7388 treatment.Results: We demonstrated that RG7388 promotes low nanomolar antiproliferative activity selectively in cell lines with wild-type p53 and p53 pathway activation, resulting in cell cycle arrest and apoptosis. In PDX models, oral administration of RG7388 led to potent dose-dependent and time-dependent activation of p53 and had a significant impact on p53 downstream targets. Daily treatment of RG7388 in mice at 50 and 80 mg/kg/day inhibited tumor growth in three wild-type p53 PDX models. Activation of the p53 pathway inhibited cell proliferation as observed by reduced Ki-67-positive cells in xenograft tumors. However, induction of apoptotic caspase activity was not observed in these tumors. Notably, RG7388 treatment remains effective in tumors lacking MDM2 amplification but expressing wild-type p53.Conclusions: MDM2 small-molecule inhibitor is effective in treating NSCLC tumors with wild-type p53, supporting further clinical investigation as a potential NSCLC therapy.