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MEK inhibition overcomes everolimus resistance in gastric cancer

Hongfang Liu1, Yang Yao1, Juan Zhang2

  • 1Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, 39 Jingzhou Street, Xiangyang, 441021, Hubei, People's Republic of China.

Cancer Chemotherapy and Pharmacology
|May 24, 2020
PubMed
Abstract

Insights

In gastric cancer, everolimus resistance is linked to increased extracellular signal-regulated kinase (ERK) activation. Combining everolimus with trametinib, an ERK inhibitor, effectively overcomes this resistance, suggesting a promising new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The mammalian target of rapamycin (mTOR) pathway is a key therapeutic target in gastric cancer.
  • Everolimus, an mTOR inhibitor, shows limited response rates in gastric cancer patients, necessitating further investigation into resistance mechanisms.

Purpose of the Study:

  • To investigate the role of extracellular signal-regulated kinase (ERK) activation in everolimus resistance in gastric cancer.
  • To evaluate the efficacy of dual inhibition of mTOR and ERK pathways in overcoming everolimus resistance.

Main Methods:

  • Western blot analysis was used to assess ERK activation.
  • In vitro cellular assays and in vivo xenograft mouse models were employed to determine the effects of combined ERK and mTOR inhibition.
  • Genetic and pharmacological approaches were utilized for dual pathway inhibition.

Main Results:

  • Everolimus treatment led to decreased phosphorylation of mTOR pathway components (mTOR, rS6, 4EBP1) and increased phosphorylation of ERK and p90RSK in gastric cancer cells.
  • Trametinib, an ERK inhibitor, demonstrated efficacy in overcoming everolimus resistance by targeting resistant cells and enhancing the efficacy of everolimus in sensitive cells.
  • Mechanism studies revealed that trametinib reverses everolimus resistance by inhibiting ERK and modulating ERK-mediated Bcl-2 family proteins.

Conclusions:

  • mTOR pathway inhibition can paradoxically activate ERK in gastric cancer, contributing to treatment resistance.
  • Trametinib effectively reverses this paradoxical ERK activation, offering a strategy to overcome everolimus resistance.
  • The combination of everolimus and trametinib holds potential for accelerating clinical trials in gastric cancer treatment.
Keywords:
Bcl-2ERKEverolimusGastric cancerTrametinibmTOR

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