PMID- 31268158
OWN - NLM
STAT- MEDLINE
DCOM- 20200113
LR  - 20200113
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 55
IP  - 2
DP  - 2019 Aug
TI  - Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal 
      stromal tumors using the Connectivity Map.
PG  - 536-546
LID - 10.3892/ijo.2019.4829 [doi]
AB  - Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that 
      commonly contain a mutation in the tyrosine kinases, KIT and platelet‑derived 
      growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all 
      effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. 
      The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector 
      of KIT and is therefore a reasonable therapeutic target for this disease. In this 
      study, we explored the potential agents targeting ETV1 in GISTs by uploading an 
      ETV1 knockout gene signature of GIST cell lines to the pattern‑matching software 
      'Connectivity Map'. The activity and mechanisms of identified agents were 
      examined using an in vitro model. Four drugs were identified: 
      Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors 
      (HDACIs)] and trifluoperazine and thioridazine (two phenothiazine‑class drugs). 
      Western blot analysis demonstrated that all four drugs had ETV1‑downregulating 
      effects. As HDACIs have been previously studied in GISTs, we focused on 
      phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce 
      apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect 
      on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead 
      upregulated extracellular‑signal‑regulated kinase (ERK) activity. A combination 
      of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. 
      Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were 
      activated/upregulated following phenothiazine treatment, and the MEK 
      inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, 
      resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, 
      the findings of this study established phenothiazine as a novel class of 
      therapeutic agents in GIST treatment and demonstrate that a combination of 
      phenothiazine and MEK inhibitor has great potential for use in the treatment of 
      GISTs.
FAU - Yen, Chueh-Chuan
AU  - Yen CC
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Chen, Li-Tzong
AU  - Chen LT
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan 70456, Taiwan, R.O.C.
FAU - Li, Chien-Feng
AU  - Li CF
AD  - Department of Pathology, Chi‑Mei Medical Center, Tainan 71004, Taiwan, R.O.C.
FAU - Chen, San-Chi
AU  - Chen SC
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Chua, Wei-Yang
AU  - Chua WY
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Lin, Yung-Chan
AU  - Lin YC
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Yen, Chiao-Han
AU  - Yen CH
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Chen, Yen-Chun
AU  - Chen YC
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Yang, Muh-Hwa
AU  - Yang MH
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Chao, Yee
AU  - Chao Y
AD  - Division of Medical Oncology, Center for Immuno‑oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
FAU - Fletcher, Jonathan A
AU  - Fletcher JA
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
LA  - eng
PT  - Journal Article
DEP - 20190621
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antiprotozoal Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (ETV1 protein, human)
RN  - 0 (Phenothiazines)
RN  - 0 (Transcription Factors)
RN  - GS9EX7QNU6 (phenothiazine)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Antiprotozoal Agents/pharmacology
MH  - Apoptosis
MH  - Biomarkers, Tumor/*genetics
MH  - *Connectome
MH  - DNA-Binding Proteins/*antagonists & inhibitors/genetics
MH  - Gastrointestinal Neoplasms/*drug therapy/genetics/pathology
MH  - Gastrointestinal Stromal Tumors/*drug therapy/genetics/pathology
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Phenothiazines/*pharmacology
MH  - Prognosis
MH  - Signal Transduction
MH  - Transcription Factors/*antagonists & inhibitors/genetics
EDAT- 2019/07/04 06:00
MHDA- 2020/01/14 06:00
CRDT- 2019/07/04 06:00
PHST- 2018/11/01 00:00 [received]
PHST- 2019/06/12 00:00 [accepted]
PHST- 2019/07/04 06:00 [pubmed]
PHST- 2020/01/14 06:00 [medline]
PHST- 2019/07/04 06:00 [entrez]
AID - 10.3892/ijo.2019.4829 [doi]
PST - ppublish
SO  - Int J Oncol. 2019 Aug;55(2):536-546. doi: 10.3892/ijo.2019.4829. Epub 2019 Jun 
      21.