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Updated: Jun 24, 2026

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
09:29

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Published on: September 30, 2016

Targeting MEK1/2 inhibits mitochondrial respiration and redox homeostasis in resistant rectal cancer

Hu Chenghao1,2, Wu Feng3, Chen Chunli3

  • 1Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. huchenghao@hbmu.edu.cn.

Journal of Bioenergetics and Biomembranes
|June 23, 2026
PubMed

Insights

MEK inhibitors like cobimetinib show promise in overcoming 5-fluorouracil resistance in rectal cancer by targeting oxidative stress and mitochondrial respiration, offering new therapeutic strategies for chemo-resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Chemo-resistance presents a significant hurdle in effective rectal cancer treatment.
  • Identifying novel therapeutic targets is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the efficacy of MEK inhibitors (cobimetinib, trametinib) against 5-fluorouracil (5-FU)-resistant rectal cancer.
  • To elucidate the underlying mechanisms of MEK inhibition in chemo-resistant rectal cancer cells.

Main Methods:

  • High-throughput drug screening to identify MEK inhibitors.
  • In vitro cytotoxicity assays and synergistic interaction studies with 5-FU.
  • Assessment of redox homeostasis, reactive oxygen species (ROS) levels, oxidative damage markers (protein carbonyl, MDA), and mitochondrial respiration (OCR).
  • In vivo studies using chemo-resistant colorectal cancer xenograft models.

Main Results:

  • Cobimetinib and trametinib demonstrated dose-dependent cytotoxicity against rectal cancer cells and synergized with 5-FU.
  • MEK inhibition led to increased ROS, oxidative damage, and decreased mitochondrial respiration.
  • Genetic MEK1/2 knockdown confirmed MEK's role in regulating oxidative stress and mitochondrial function.
  • In vivo, MEK inhibitors suppressed tumor growth in chemo-resistant models with minimal toxicity.

Conclusions:

  • MEK inhibitors are effective in overcoming 5-FU resistance in rectal cancer models.
  • Targeting MEK impacts oxidative stress and mitochondrial respiration, offering a novel therapeutic approach.
  • Cobimetinib and trametinib show potential as adjunct therapies for chemo-resistant rectal cancer.
Keywords:
5-FU resistanceMEK inhibitionMitochondrial respirationOxidative stressRectal cancer

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