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The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma

Mikhail S Chesnokov1, Imran Khan1, Yeonjung Park2

  • 1The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.

Cancers
|April 3, 2021
PubMed

Insights

MEK1/2 pathway inhibition with trametinib suppresses high-grade serous ovarian carcinoma (HGSOC) growth but may increase cancer stem cell properties. Combination therapy is suggested for maintenance treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • High-grade serous ovarian carcinoma (HGSOC) is a lethal gynecological cancer with high recurrence and chemoresistance.
  • The RAS/MEK/ERK pathway is implicated in cancer proliferation and resistance, yet its role in HGSOC remains understudied.

Purpose of the Study:

  • To investigate the activity of the MEK1/2-ERK1/2 pathway in HGSOC.
  • To evaluate the efficacy of MEK1/2 inhibition using trametinib in HGSOC models.
  • To explore the impact of MEK1/2 inhibition on cancer stem cell populations and potential resistance mechanisms.

Main Methods:

  • Analysis of MEK1/2 pathway activity in clinical HGSOC samples and cell lines via immunohistochemistry, immunoblotting, and RT-qPCR.
  • In vitro assessment of trametinib's effects on HGSOC cell lines, including cell cycle, cell death, and stemness markers.
  • In vivo evaluation of trametinib's impact on tumor growth using mouse xenograft models.

Main Results:

  • The MEK1/2 pathway is hyperactivated in HGSOC and further stimulated by cisplatin.
  • Trametinib treatment resulted in G1/G0 cell cycle arrest and reduced tumor growth in vivo.
  • Trametinib did not induce cell death or decrease CD133+ cells but increased stemness gene expression and aldehyde dehydrogenase (ALDH)1 activity, promoting survival in non-adherent conditions.

Conclusions:

  • MEK1/2 inhibition shows promise as a maintenance therapy to suppress ovarian cancer growth.
  • Trametinib treatment can promote stem-like properties, suggesting a potential resistance mechanism.
  • Combination therapy targeting both MEK1/2 and cancer stem cells (CSCs) should be considered to overcome resistance.
Keywords:
MEK1/2cancer stem-like cellshigh-grade serous ovarian carcinomaproliferationtrametinib

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