A Subset of Diffuse-type Gastric Cancer is Susceptible to MTOR Inhibitors and Checkpoint Inhibitors

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2019 Mar 15

PMID 30866995

Citations 18

Authors

Hiroshi Fukamachi

Seon-Kyu Kim

Jiwon Koh

Hye Seung Lee

Yasushi Sasaki

Kentaro Yamashita

Taketo Nishikawaji

Shu Shimada

Yoshimitsu Akiyama

Sun-Ju Byeon

Dong-Hyuck Bae

Keisuke Okuno

Masatoshi Nakagawa

Toshiro Tanioka

Mikito Inokuchi

Hiroshi Kawachi

Kiichiro Tsuchiya

Kazuyuki Kojima

Takashi Tokino

Yoshinobu Eishi

Yong Sung Kim

Woo Ho Kim

Yasuhito Yuasa

Shinji Tanaka

Affiliations

Soon will be listed here.

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.

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