The mek1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Mikhail S. Chesnokov, Imran Khan, Yeonjung Park, Jessica Ezell, Geeta Mehta, Abdelrahman Yousif, Linda J. Hong, Ronald J. Buckanovich, Akimasa Takahashi, Ilana Chefetz

Research output: Contribution to journalArticlepeer-review

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 tram-etinib 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.

Original languageEnglish (US)
Article number1369
Pages (from-to)1-20
Number of pages20
JournalCancers
Volume13
Issue number6
DOIs
StatePublished - Mar 2 2021

Bibliographical note

Funding Information:
Funding: This research was funded in part by the Michigan Ovarian Cancer Alliance (MIOCA) and The Foundation for Women’s Cancer (FWC) awards to I.C., R.J.B is supported by NIH NCI 1R01CA238315.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Cancer stem-like cells
  • High-grade serous ovarian carcinoma
  • MEK1/2
  • Proliferation
  • Trametinib

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