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Cancer Chemotherapy and Pharmacology

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01-06-2020 | Gastric Cancer | Original Article

MEK inhibition overcomes everolimus resistance in gastric cancer

Authors: Hongfang Liu, Yang Yao, Juan Zhang, Jing Li

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2020

Abstract

Background

Although substantial evidence has shown that the mammalian target of rapamycin (mTOR) pathway is an important therapeutic target in gastric cancer, the overall response rates in patients to mTOR inhibitor everolimus have been less than initially expected. We hypothesized that the limited efficacy of everolimus in gastric cancer is due to the activation of extracellular signal-regulated kinase (ERK).

Methods

ERK activation was investigated using western blot. The effects of dual inhibition of ERK and mTOR via genetic and pharmacological approaches were determined using cellular assays and xenograft mouse model.

Results

We observed the decreased phosphorylation of mTOR, rS6, and 4EBP1 and increased phosphorylation of ERK and p90RSK in gastric cancer cells exposed to everolimus at clinically relevant concentration. Using both in vitro cell culture assays and in vivo xenograft mouse model, we found that trametinib overcame everolimus resistance by either effectively targeting resistant cells or further enhancing everolimus’ efficacy in sensitive cells. Mechanism studies confirmed that trametinib overcame everolimus resistance via specifically inhibiting ERK and regulating ERK-mediated Bcl-2 family proteins in gastric cancer cells.

Conclusions

Inhibition of mTOR pathway can induce “paradoxical” activation of ERK in gastric cancer, and this activation can be reversed by trametinib. Since both drugs are clinically available, our findings might accelerate the initiation of clinical trials on gastric cancer using everolimus and trametinib combination.

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Title: MEK inhibition overcomes everolimus resistance in gastric cancer
Authors: Hongfang Liu
Yang Yao
Juan Zhang
Jing Li
Publication date: 01-06-2020
Publisher: Springer Berlin Heidelberg
Keywords: Gastric Cancer
Gastric Cancer
Everolimus
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04078-0

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Abstract

Background

Methods

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Conclusions

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