RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors.
RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors.
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DOI：
10.1158/2159-8290.cd-14-0971
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发表时间：
2015-12
期刊：
影响因子：
28.2
通讯作者：
Perez-Soler R
中科院分区：
文献类型：
--
作者：
Cheng H;Zou Y;Ross JS;Wang K;Liu X;Halmos B;Ali SM;Liu H;Verma A;Montagna C;Chachoua A;Goel S;Schwartz EL;Zhu C;Shan J;Yu Y;Gritsman K;Yelensky R;Lipson D;Otto G;Hawryluk M;Stephens PJ;Miller VA;Piperdi B;Perez-Soler R
我们发现，在一名18岁不吸烟的肺腺癌患者中，作为mTORC2关键组分的RICTOR扩增是唯一可采取行动的基因组改变。在癌症基因组图谱（TCGA）中，13%的肺癌（1016例）存在这种情况，在通过基因组分析确定的1070名患者的独立队列中，其频率相似。在后一系列中，11%的病例存在RICTOR扩增且为唯一相关的基因组改变。通过在体外和体内敲除RICTOR后肺癌细胞生长减缓，以及RICTOR在Ba/F3细胞系中的转化能力，表明了其致癌作用。与针对PI3K/AKT/mTOR通路的其他药物相比，mTOR1/2抑制剂对RICTOR扩增的肺癌细胞活性显著更强。此外，还观察到RICTOR扩增与对mTOR1/2抑制剂敏感性之间存在关联。该指标病例患者接受mTOR1/2抑制剂治疗后，肿瘤稳定了18个多月。
We identified amplification of RICTOR, a key component of the mTORC2, as the sole actionable genomic alteration in an 18-year-old never smoker with lung adenocarcinoma. It occurs in 13% of lung cancers (1016 cases) in TCGA and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling. In the latter series, 11% of cases harbored RICTOR amplification as the only relevant genomic alteration. Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the transforming capacity of RICTOR in a Ba/F3-cell system. The mTOR1/2 inhibitors were significantly more active against RICTOR-amplified lung cancer cells as compared to other agents targeting the PI3K/AKT/mTOR pathway. Moreover, an association between RICTOR amplification and sensitivities to mTOR1/2 inhibitors was observed. The index patient has been treated with mTOR1/2 inhibitors that led to tumor stabilization for over 18 months.