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The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma.
Chesnokov, Mikhail S; Khan, Imran; Park, Yeonjung; Ezell, Jessica; Mehta, Geeta; Yousif, Abdelrahman; Hong, Linda J; Buckanovich, Ronald J; Takahashi, Akimasa; Chefetz, Ilana.
Afiliación
  • Chesnokov MS; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • Khan I; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • Park Y; Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Ezell J; Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Mehta G; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
  • Yousif A; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • Hong LJ; Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
  • Buckanovich RJ; Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Takahashi A; Division of Hematology Oncology, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Chefetz I; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Cancers (Basel) ; 13(6)2021 Mar 18.
Article en En | MEDLINE | ID: mdl-33803586
ABSTRACT
High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.
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