A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors
A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors
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DOI：
10.1186/s13046-019-1121-3
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发表时间：
2019-03-12
影响因子：
11.3
通讯作者：
Tanaka, Shinji
中科院分区：
文献类型：
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作者：
Fukamachi, Hiroshi;Kim, Seon-Kyu;Tanaka, Shinji
研究背景雷帕霉素（mTOR）信号通路在胃癌（GC）的发生、发展中起重要作用，但mTOR抑制剂依维莫司对GC的治疗效果不佳。癌症基因组图谱（TCGA）的研究人员报告说，大多数弥漫型GC是基因组稳定的（GS）。病理学分析表明，一些弥漫型GC开发从patientinal-type GCs.MethodsWe建立了患者来源的异种移植（PDX）线从弥漫型GC，并寻找抑制其生长的药物。结果mTOR抑制剂temsirolimus可明显抑制PDX源性弥漫型GC起始细胞的生长，其生长受Wnt-mTOR轴调控。这些细胞是微卫星不稳定（MSI）或染色体不稳定（CIN），与TCGA报告不一致。TCGA组弥漫型GC可分为两组，Ⅰ组以GS亚型为主，Ⅱ组以CIN和MSI亚型为主，其中包括PDX源性弥漫型GC细胞。我们通过鉴定TCGA队列中的PIK 3CA突变和MSI状况，估计簇II中约9%和55%的弥漫型GC分别是mTOR抑制剂和检查点抑制剂的应答者。这些比率远大于I群中弥漫型GC或弥漫型GC。进一步的分析表明，弥漫型GC在集群II开发从pneuminal-type GCs，而那些在集群I从正常gastric epithelial cells.ConclusionmTOR抑制剂和检查点抑制剂可能是有用的治疗的一个子集的弥漫型GC，可能发展从pneuminal-type GCs。
BackgroundMechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs.MethodsWe established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles.ResultsmTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells.ConclusionmTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.