Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism.

Abstract

Trastuzumab shows remarkable efficacy in treatment of ErbB2-positive breast cancers when used alone or in combination with other chemotherapeutics. However, acquired resistance develops in most treated patients, necessitating alternate treatment strategies. Increased aerobic glycolysis is a hallmark of cancer and inhibition of glycolysis may offer a promising strategy to preferentially kill cancer cells. In this study, we investigated the antitumor effects of trastuzumab in combination with glycolysis inhibitors in ErbB2-positive breast cancer. We found that trastuzumab inhibits glycolysis via downregulation of heat shock factor 1 (HSF1) and lactate dehydrogenase A (LDH-A) in ErbB2-positive cancer cells, resulting in tumor growth inhibition. Moreover, increased glycolysis via HSF1 and LDH-A contributes to trastuzumab resistance. Importantly, we found that combining trastuzumab with glycolysis inhibition synergistically inhibited trastuzumab-sensitive and -resistant breast cancers in vitro and in vivo, due to more efficient inhibition of glycolysis. Taken together, our findings show how glycolysis inhibition can dramatically enhance the therapeutic efficacy of trastuzumab in ErbB2-positive breast cancers, potentially useful as a strategy to overcome trastuzumab resistance.

• Authors: Yuhua Zhao, Hao Liu, Zixing Liu, Yan Ding, Susan P Ledoux, Glenn L Wilson, Richard Voellmy, Yifeng Lin, Wensheng Lin, Rita Nahta, Bolin Liu, Oystein Fodstad, Jieqing Chen, Yun Wu, Janet E Price, Ming Tan
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 13 Pg. 4585-97 (Jul 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21498634 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• DNA-Binding Proteins
• HSF1 protein, human
• Heat Shock Transcription Factors
• Isoenzymes
• Organic Chemicals
• Transcription Factors
• oxamate (repellent)
• Deoxyglucose
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• Receptor, ErbB-2
• Glucose
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• DNA-Binding Proteins (metabolism)
• Deoxyglucose (pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Glucose (metabolism)
• Glycolysis (drug effects)
• Heat Shock Transcription Factors
• Humans
• Isoenzymes (metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Lactate Dehydrogenase 5
• Mammary Neoplasms, Experimental (drug therapy, metabolism)
• Mice
• Mice, Nude
• Organic Chemicals (pharmacology)
• Receptor, ErbB-2 (metabolism)
• Transcription Factors (metabolism)
• Trastuzumab