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Targeting RAS-ERK pathway alterations with MEK inhibitors to improve chemosensitivity in high grade serous ovarian

Nancy T Nguyen1, Alan Raetz2, Dennis Montoya2

  • 1University of California Davis, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, USA.

Gynecologic Oncology
|October 8, 2023
PubMed
Abstract

Insights

MEK inhibitors can block the RAS-ERK pathway in platinum-resistant high-grade serous ovarian cancer (HGSOC). Combining MEK inhibitors with carboplatin shows synergistic effects, potentially improving platinum sensitivity in HGSOC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • High-grade serous ovarian cancer (HGSOC) often develops resistance to platinum-based chemotherapy.
  • The RAS-ERK signaling pathway plays a role in cancer cell survival and drug resistance.
  • Adaptive resistance mechanisms can limit the efficacy of chemotherapy in HGSOC.

Purpose of the Study:

  • To investigate whether blocking the RAS-ERK pathway with MEK inhibitors can overcome platinum resistance in HGSOC.
  • To assess the synergistic effects of combining MEK inhibitors with carboplatin in platinum-resistant HGSOC models.

Main Methods:

  • Utilized HGSOC cell lines and patient-derived organoids (PDOs) from platinum-resistant tumors.
  • Treated models with carboplatin and MEK inhibitors (cobimetinib, trametinib) alone and in combination.
  • Evaluated cytotoxic effects, confirmed pathway blockade via Western blot, and analyzed gene expression changes using RNA sequencing.

Main Results:

  • MEK inhibitors, particularly cobimetinib, demonstrated cytotoxicity and effectively blocked the RAS-ERK pathway in HGSOC models.
  • Combination therapy showed synergistic cytotoxic effects, most notably with carboplatin and cobimetinib in OVSAHO cells (harboring an NF1 mutation).
  • RNA sequencing revealed downregulation of c-MYC and FOXM1 following MEK inhibitor treatment, and NF1 knockdown increased platinum resistance.

Conclusions:

  • MEK inhibitors successfully inhibit the RAS-ERK pathway in platinum-resistant HGSOC cells and PDOs.
  • Combination of MEK inhibitors with carboplatin demonstrates select synergistic effects, suggesting a potential strategy to enhance platinum sensitivity in HGSOC.
Keywords:
MEK inhibitorsPlatinum resistant ovarian cancer

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