Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose

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Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose Metabolism

1. Yuhua Zhao1,3,
2. Hao Liu1,
3. Zixing Liu1,
4. Yan Ding1,
5. Susan P. LeDoux2,
6. Glenn L. Wilson2,
7. Richard Voellmy4,
8. Yifeng Lin2,
9. Wensheng Lin2,
10. Rita Nahta5,
11. Bolin Liu6,
12. Oystein Fodstad7,
13. Jieqing Chen8,
14. Yun Wu8,
15. Janet E. Price9, and
16. Ming Tan1,2

+ Author Affiliations

1. Authors' Affiliations:¹Mitchell Cancer Institute, ²Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama; ³Department of Biochemistry and Molecular Biology, West China Medical Center, Sichuan University, Chengdu, China; ⁴HSF Pharmaceuticals S.A., La Tour-de-Peilz, Switzerland; ⁵Department of Pharmacology, Emory University, Atlanta, Georgia; ⁶Department of Pathology, University of Colorado, Denver, Colorado; ⁷Department of Tumor Biology, Norwegian Radium Hospital, University of Oslo, Oslo, Norway; and Departments of ⁸Pathology and ⁹Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas

1. Corresponding Author:
   Ming Tan, Mitchell Cancer Institute, University of South Alabama, 1660 Spring Hill Avenue, Mobile, AL 36604. Phone: 251-460-6993; Fax: 251-460-6994; E-mail: mtan@usouthal.edu

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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. Cancer Res; 71(13); 4585–97. ©2011 AACR.