Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism

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

Research output: Contribution to journalArticlepeer-review

164 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4585-4597
Number of pages13
JournalCancer Research
Volume71
Issue number13
DOIs
StatePublished - Jul 1 2011

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