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Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism

Yuhua Zhao1, Hao Liu, Zixing Liu

  • 1Mitchell Cancer Institute, Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama 36604, USA.

Cancer Research
|April 19, 2011
PubMed

Insights

Combining trastuzumab with glycolysis inhibitors enhances breast cancer treatment. This strategy overcomes resistance by targeting aerobic glycolysis, offering a new approach for ErbB2-positive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Trastuzumab is effective against ErbB2-positive breast cancer but acquired resistance limits its long-term use.
  • Increased aerobic glycolysis is a key metabolic adaptation in cancer cells.
  • Targeting cancer cell metabolism, specifically glycolysis, presents a potential therapeutic strategy.

Purpose of the Study:

  • To investigate the antitumor effects of combining trastuzumab with glycolysis inhibitors in ErbB2-positive breast cancer.
  • To explore the role of aerobic glycolysis and its regulators (HSF1, LDH-A) in trastuzumab efficacy and resistance.
  • To evaluate the synergistic potential of combined therapy in both trastuzumab-sensitive and -resistant models.

Main Methods:

  • In vitro and in vivo studies using ErbB2-positive breast cancer models.
  • Assessment of glycolysis inhibition by trastuzumab through heat shock factor 1 (HSF1) and lactate dehydrogenase A (LDH-A) downregulation.
  • Combination therapy experiments with trastuzumab and glycolysis inhibitors.

Main Results:

  • Trastuzumab treatment led to tumor growth inhibition by downregulating HSF1 and LDH-A, thereby inhibiting glycolysis.
  • Upregulation of glycolysis via HSF1 and LDH-A was identified as a mechanism contributing to trastuzumab resistance.
  • Combined treatment with trastuzumab and glycolysis inhibitors demonstrated synergistic antitumor effects in vitro and in vivo, overcoming resistance.

Conclusions:

  • Glycolysis inhibition significantly enhances trastuzumab's therapeutic efficacy in ErbB2-positive breast cancers.
  • This combination strategy shows promise for overcoming acquired trastuzumab resistance.
  • Targeting aerobic glycolysis represents a viable approach to improve treatment outcomes for breast cancer patients.

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