title: 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.affiliation: Mitchell Cancer Institute, Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Zixing
authors.initials: Z
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Susan P
authors.initials: SP
authors.lastname: Ledoux
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Wilson
authors.forename: Richard
authors.initials: R
authors.lastname: Voellmy
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Lin
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lin
authors.forename: Rita
authors.initials: R
authors.lastname: Nahta
authors.forename: Bolin
authors.initials: B
authors.lastname: Liu
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.forename: Jieqing
authors.initials: J
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Janet E
authors.initials: JE
authors.lastname: Price
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009930:Organic Chemicals / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D003847:Deoxyglucose; D005947:Glucose; D000076249:Heat Shock Transcription Factors; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D009930:Organic Chemicals; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; C000619706:HSF1 protein, human; C048603:oxamate (repellent)