PMID- 30866995
OWN - NLM
STAT- MEDLINE
DCOM- 20190723
LR  - 20211204
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 38
IP  - 1
DP  - 2019 Mar 12
TI  - A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and 
      checkpoint inhibitors.
PG  - 127
LID - 10.1186/s13046-019-1121-3 [doi]
LID - 127
AB  - 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.
FAU - Fukamachi, Hiroshi
AU  - Fukamachi H
AD  - Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan. hfukama.monc@gmail.com.
FAU - Kim, Seon-Kyu
AU  - Kim SK
AD  - Personalized Genomic Medicine Research Center, Korea Research Institute of 
      Bioscience and Biotechnology, Daejeon, Korea.
FAU - Koh, Jiwon
AU  - Koh J
AD  - Department of Pathology, Seoul National University Bundang Hospital, Gyeonggi-do, 
      Korea.
FAU - Lee, Hye Seung
AU  - Lee HS
AD  - Department of Pathology, Seoul National University Bundang Hospital, Gyeonggi-do, 
      Korea.
FAU - Sasaki, Yasushi
AU  - Sasaki Y
AD  - Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo 
      Medical University School of Medicine, Sapporo, Japan.
FAU - Yamashita, Kentaro
AU  - Yamashita K
AD  - Department of Gastroenterology and Hepatology, Sapporo Medical University School 
      of Medicine, Sapporo, Japan.
FAU - Nishikawaji, Taketo
AU  - Nishikawaji T
AD  - Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan.
AD  - Present Address: Division of Cancer Biology and Therapeutics, Miyagi Cancer 
      Center Research Institute, Miyagi, 981-1293, Japan.
FAU - Shimada, Shu
AU  - Shimada S
AD  - Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Akiyama, Yoshimitsu
AU  - Akiyama Y
AD  - Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Byeon, Sun-Ju
AU  - Byeon SJ
AD  - Department of Pathology, Seoul National University College of Medicine, Seoul, 
      Korea.
FAU - Bae, Dong-Hyuck
AU  - Bae DH
AD  - Genome Editing Research Center, Korea Research Institute of Bioscience & 
      Biotechnology, Daejeon, Korea.
FAU - Okuno, Keisuke
AU  - Okuno K
AD  - Department of Gastrointestinal Surgery, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Nakagawa, Masatoshi
AU  - Nakagawa M
AD  - Department of Gastrointestinal Surgery, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Tanioka, Toshiro
AU  - Tanioka T
AD  - Department of Gastrointestinal Surgery, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Inokuchi, Mikito
AU  - Inokuchi M
AD  - Department of Gastrointestinal Surgery, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Kawachi, Hiroshi
AU  - Kawachi H
AD  - Department of Human Pathology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan.
AD  - Present Address: Department of Pathology, The Cancer Institute Hospital of the 
      Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
FAU - Tsuchiya, Kiichiro
AU  - Tsuchiya K
AD  - Department of Gastroenterology and Hepatology, Tokyo Medical and Dental 
      University, Tokyo, Japan.
FAU - Kojima, Kazuyuki
AU  - Kojima K
AD  - Center of Minimally Invasive Surgery, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Tokino, Takashi
AU  - Tokino T
AD  - Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo 
      Medical University School of Medicine, Sapporo, Japan.
FAU - Eishi, Yoshinobu
AU  - Eishi Y
AD  - Department of Human Pathology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Kim, Yong Sung
AU  - Kim YS
AD  - Genome Editing Research Center, Korea Research Institute of Bioscience & 
      Biotechnology, Daejeon, Korea.
FAU - Kim, Woo Ho
AU  - Kim WH
AD  - Department of Pathology, Seoul National University College of Medicine, Seoul, 
      Korea.
FAU - Yuasa, Yasuhito
AU  - Yuasa Y
AD  - Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Tanaka, Shinji
AU  - Tanaka S
AD  - Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, Japan.
LA  - eng
GR  - JP15K06832/Japan Society for the Promotion of Science/
GR  - JP25253081/Japan Society for the Promotion of Science/
GR  - JP16H06276/Japan Society for the Promotion of Science/
GR  - 16K08661/Japan Society for the Promotion of Science/
GR  - AA005/Japan Society for the Promotion of Science/
GR  - JP17ck0106017/Japan Agency for Medical Research and Development/
GR  - 221S0001/Ministry of Education, Culture, Sports, Science and Technology/
GR  - KRIBB Research Initiative Program/Korea Research Institute of Bioscience and 
      Biotechnology/
PT  - Journal Article
DEP - 20190312
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Microsatellite Instability
MH  - Stomach Neoplasms/*drug therapy/pathology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC6416873
OTO - NOTNLM
OT  - Diffuse-type gastric cancer
OT  - Immune checkpoint inhibitor
OT  - Microsatellite unstable
OT  - PD-L1
OT  - PIK3CA
OT  - Patient-derived xenograft
OT  - Primary culture
OT  - Temsirolimus
OT  - mTOR inhibitor
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study was approved by the 
      Medical Research Ethics Committee for Genetic Research of Tokyo Medical and 
      Dental University, and informed consent was obtained from all patients. This 
      study was also approved by Institutional Review Boards for Human Subject Research 
      at Seoul National University Hospital and Seoul National University Bundang 
      Hospital, and informed consent was obtained from all patients in both institutes. 
      This research was approved by the Institutional Animal Care and Use Committee of 
      Tokyo Medical and Dental University, and animals used in the present study were 
      maintained in accordance with the Guideline for Care and Use of Laboratory 
      Animals of the Institutional Animal Care and Use Committees of Tokyo Medical and 
      Dental University. CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: 
      The authors declare that they have no competing interests. PUBLISHER'S NOTE: 
      Springer Nature remains neutral with regard to jurisdictional claims in published 
      maps and institutional affiliations.
EDAT- 2019/03/15 06:00
MHDA- 2019/07/25 06:00
PMCR- 2019/03/12
CRDT- 2019/03/15 06:00
PHST- 2019/01/17 00:00 [received]
PHST- 2019/02/28 00:00 [accepted]
PHST- 2019/03/15 06:00 [entrez]
PHST- 2019/03/15 06:00 [pubmed]
PHST- 2019/07/25 06:00 [medline]
PHST- 2019/03/12 00:00 [pmc-release]
AID - 10.1186/s13046-019-1121-3 [pii]
AID - 1121 [pii]
AID - 10.1186/s13046-019-1121-3 [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2019 Mar 12;38(1):127. doi: 10.1186/s13046-019-1121-3.