Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis.
Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis.
复制标题
DOI：
10.1097/jto.0000000000000250
复制
发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Goto K
中科院分区：
文献类型：
--
作者：
Umemura S;Mimaki S;Makinoshima H;Tada S;Ishii G;Ohmatsu H;Niho S;Yoh K;Matsumoto S;Takahashi A;Morise M;Nakamura Y;Ochiai A;Nagai K;Iwakawa R;Kohno T;Yokota J;Ohe Y;Esumi H;Tsuchihara K;Goto K
有关小细胞肺癌（SCLC）治疗相关基因组改变的信息尚未得到充分开发。我们使用综合方法对 SCLC 基因组进行了分析，以对可靶向的改变进行分层。我们对手术切除的肿瘤和来自未经治疗的日本 SCLC 患者的匹配正常组织样本进行了全外显子测序 (n = 51) 和拷贝数分析 (n = 47)。本研究纳入的 51 名患者的人口统计数据如下：中位年龄 67 岁（范围 42-86 岁）；女性，9 人（18%）；有吸烟史，50（98%）；病理分期I/II/III/IV，分别为28/13/9/1。非同义突变的平均数量为 209（范围，41-639；标准差，130）。我们反复证实了 TP53 和 RB1 失活突变的高发生率以及 MYC 家族成员的扩增。此外，在 36% 的肿瘤中检测到 PI3K/AKT/mTOR 通路的基因改变：PIK3CA，6%； PTEN，4%； AKT2，9%； AKT3，4%；里克托，9%； mTOR，4%。此外，这条途径中的个体变化是相互排斥的。重要的是，含有活性 PIK3CA 突变的 SCLC 细胞可能是目前可用的 PI3K 抑制剂的靶标。 PI3K/AKT/mTOR 通路在 SCLC 基因组改变中是可区分的。因此，基于测序的综合分析可以根据潜在的治疗靶点对 SCLC 患者进行分层。
The information regarding therapeutically relevant genomic alterations in small cell lung cancer (SCLC) is not well developed. We analyzed the SCLC genome using an integrative approach to stratify the targetable alterations. We performed whole exon sequencing (n = 51) and copy number analysis (n =47) on surgically resected tumors and matched normal tissue samples from treatment-naive Japanese SCLC patients. The demographics of the 51 patients included in this study were as follows: median age, 67 years (range, 42–86 years); female, 9 (18%); history of smoking, 50 (98%); and pathological stage I/II/III/IV, 28/13/9/1, respectively. The average number of nonsynonymous mutations was 209 (range, 41–639; standard deviation, 130). We repeatedly confirmed the high prevalence of inactivating mutations in TP53 and RB1, and the amplification of MYC family members. In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 36% of the tumors: PIK3CA, 6%; PTEN, 4%; AKT2, 9%; AKT3, 4%; RICTOR, 9%; and mTOR, 4%. Furthermore, the individual changes in this pathway were mutually exclusive. Importantly, the SCLC cells harboring active PIK3CA mutations were potentially targetable with currently available PI3K inhibitors. The PI3K/AKT/mTOR pathway is distinguishable in SCLC genomic alterations. Therefore, a sequencing-based comprehensive analysis could stratify SCLC patients by potential therapeutic targets.