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Title 

A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors

Authors 

H FukamachiSeon-Kyu KimJ KohH S LeeY SasakiK YamashitaT NishikawajiS ShimadaY AkiyamaS J ByeonDong Hyuck BaeK OkunoM NakagawaT TaniokaM InokuchiH KawachiK TsuchiyaK KojimaT TokinoY EishiYong Sung KimW H KimY YuasaS Tanaka

Publisher 

BioMed Central

Issue Date 

2019

Citation 

Journal of Experimental and Clinical Cancer Research

Keywords 

Diffuse-type gastric cancerImmune checkpoint inhibitorMicrosatellite unstablePD-L1PIK3CAPatient-derived xenograftPrimary cultureTemsirolimusmTOR inhibitor

Abstract 

BACKGROUND: Mechanistic 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. METHODS: We 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. RESULTS: mTOR 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. CONCLUSION: mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.

URI 

https://doi.org/10.1186/s13046-019-1121-3

ISSN 

1756-9966

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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