Rich66
07-07-2011, 09:59 PM
Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose Metabolism
Yuhua Zhao (http://cancerres.aacrjournals.org/search?author1=Yuhua+Zhao&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),3 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Hao Liu (http://cancerres.aacrjournals.org/search?author1=Hao+Liu&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Zixing Liu (http://cancerres.aacrjournals.org/search?author1=Zixing+Liu&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Yan Ding (http://cancerres.aacrjournals.org/search?author1=Yan+Ding&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Susan P. LeDoux (http://cancerres.aacrjournals.org/search?author1=Susan+P.+LeDoux&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Glenn L. Wilson (http://cancerres.aacrjournals.org/search?author1=Glenn+L.+Wilson&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Richard Voellmy (http://cancerres.aacrjournals.org/search?author1=Richard+Voellmy&sortspec=date&submit=Submit)4 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Yifeng Lin (http://cancerres.aacrjournals.org/search?author1=Yifeng+Lin&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Wensheng Lin (http://cancerres.aacrjournals.org/search?author1=Wensheng+Lin&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Rita Nahta (http://cancerres.aacrjournals.org/search?author1=Rita+Nahta&sortspec=date&submit=Submit)5 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Bolin Liu (http://cancerres.aacrjournals.org/search?author1=Bolin+Liu&sortspec=date&submit=Submit)6 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Oystein Fodstad (http://cancerres.aacrjournals.org/search?author1=Oystein+Fodstad&sortspec=date&submit=Submit)7 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Jieqing Chen (http://cancerres.aacrjournals.org/search?author1=Jieqing+Chen&sortspec=date&submit=Submit)8 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Yun Wu (http://cancerres.aacrjournals.org/search?author1=Yun+Wu&sortspec=date&submit=Submit)8 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Janet E. Price (http://cancerres.aacrjournals.org/search?author1=Janet+E.+Price&sortspec=date&submit=Submit)9 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1), and
Ming Tan (http://cancerres.aacrjournals.org/search?author1=Ming+Tan&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1)
+ (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#) Author Affiliations
<address>Authors' Affiliations:<sup>1</sup>Mitchell Cancer Institute, <sup>2</sup>Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama; <sup>3</sup>Department of Biochemistry and Molecular Biology, West China Medical Center, Sichuan University, Chengdu, China; <sup>4</sup>HSF Pharmaceuticals S.A., La Tour-de-Peilz, Switzerland; <sup>5</sup>Department of Pharmacology, Emory University, Atlanta, Georgia; <sup>6</sup>Department of Pathology, University of Colorado, Denver, Colorado; <sup>7</sup>Department of Tumor Biology, Norwegian Radium Hospital, University of Oslo, Oslo, Norway; and Departments of <sup>8</sup>Pathology and <sup>9</sup>Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas </address>
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
LINK (http://cancerres.aacrjournals.org/content/71/13/4585.abstract)
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.
Yuhua Zhao (http://cancerres.aacrjournals.org/search?author1=Yuhua+Zhao&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),3 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Hao Liu (http://cancerres.aacrjournals.org/search?author1=Hao+Liu&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Zixing Liu (http://cancerres.aacrjournals.org/search?author1=Zixing+Liu&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Yan Ding (http://cancerres.aacrjournals.org/search?author1=Yan+Ding&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Susan P. LeDoux (http://cancerres.aacrjournals.org/search?author1=Susan+P.+LeDoux&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Glenn L. Wilson (http://cancerres.aacrjournals.org/search?author1=Glenn+L.+Wilson&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Richard Voellmy (http://cancerres.aacrjournals.org/search?author1=Richard+Voellmy&sortspec=date&submit=Submit)4 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Yifeng Lin (http://cancerres.aacrjournals.org/search?author1=Yifeng+Lin&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Wensheng Lin (http://cancerres.aacrjournals.org/search?author1=Wensheng+Lin&sortspec=date&submit=Submit)2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Rita Nahta (http://cancerres.aacrjournals.org/search?author1=Rita+Nahta&sortspec=date&submit=Submit)5 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Bolin Liu (http://cancerres.aacrjournals.org/search?author1=Bolin+Liu&sortspec=date&submit=Submit)6 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Oystein Fodstad (http://cancerres.aacrjournals.org/search?author1=Oystein+Fodstad&sortspec=date&submit=Submit)7 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Jieqing Chen (http://cancerres.aacrjournals.org/search?author1=Jieqing+Chen&sortspec=date&submit=Submit)8 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Yun Wu (http://cancerres.aacrjournals.org/search?author1=Yun+Wu&sortspec=date&submit=Submit)8 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),
Janet E. Price (http://cancerres.aacrjournals.org/search?author1=Janet+E.+Price&sortspec=date&submit=Submit)9 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1), and
Ming Tan (http://cancerres.aacrjournals.org/search?author1=Ming+Tan&sortspec=date&submit=Submit)1 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1),2 (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#aff-1)
+ (http://cancerres.aacrjournals.org/content/71/13/4585.abstract#) Author Affiliations
<address>Authors' Affiliations:<sup>1</sup>Mitchell Cancer Institute, <sup>2</sup>Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama; <sup>3</sup>Department of Biochemistry and Molecular Biology, West China Medical Center, Sichuan University, Chengdu, China; <sup>4</sup>HSF Pharmaceuticals S.A., La Tour-de-Peilz, Switzerland; <sup>5</sup>Department of Pharmacology, Emory University, Atlanta, Georgia; <sup>6</sup>Department of Pathology, University of Colorado, Denver, Colorado; <sup>7</sup>Department of Tumor Biology, Norwegian Radium Hospital, University of Oslo, Oslo, Norway; and Departments of <sup>8</sup>Pathology and <sup>9</sup>Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas </address>
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
LINK (http://cancerres.aacrjournals.org/content/71/13/4585.abstract)
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.