Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal stromal tumors using the Connectivity Map

  • Authors:
    • Chueh‑Chuan Yen
    • Li‑Tzong Chen
    • Chien‑Feng Li
    • San‑Chi Chen
    • Wei‑Yang Chua
    • Yung‑Chan Lin
    • Chiao‑Han Yen
    • Yen‑Chun Chen
    • Muh‑Hwa Yang
    • Yee Chao
    • Jonathan A. Fletcher
  • View Affiliations

  • Published online on: June 21, 2019     https://doi.org/10.3892/ijo.2019.4829
  • Pages: 536-546
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

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.
View Figures
View References

Related Articles

Journal Cover

August-2019
Volume 55 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Yen CC, Chen LT, Li CF, Chen SC, Chua WY, Lin YC, Yen CH, Chen YC, Yang MH, Chao Y, Chao Y, et al: Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal stromal tumors using the Connectivity Map. Int J Oncol 55: 536-546, 2019
APA
Yen, C., Chen, L., Li, C., Chen, S., Chua, W., Lin, Y. ... Fletcher, J.A. (2019). Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal stromal tumors using the Connectivity Map. International Journal of Oncology, 55, 536-546. https://doi.org/10.3892/ijo.2019.4829
MLA
Yen, C., Chen, L., Li, C., Chen, S., Chua, W., Lin, Y., Yen, C., Chen, Y., Yang, M., Chao, Y., Fletcher, J. A."Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal stromal tumors using the Connectivity Map". International Journal of Oncology 55.2 (2019): 536-546.
Chicago
Yen, C., Chen, L., Li, C., Chen, S., Chua, W., Lin, Y., Yen, C., Chen, Y., Yang, M., Chao, Y., Fletcher, J. A."Identification of phenothiazine as an ETV1‑targeting agent in gastrointestinal stromal tumors using the Connectivity Map". International Journal of Oncology 55, no. 2 (2019): 536-546. https://doi.org/10.3892/ijo.2019.4829