TY - JOUR
T1 - Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism
AU - Zhao, Yuhua
AU - Liu, Hao
AU - Liu, Zixing
AU - Ding, Yan
AU - LeDoux, Susan P.
AU - Wilson, Glenn L.
AU - Voellmy, Richard
AU - Lin, Yifeng
AU - Lin, Wensheng
AU - Nahta, Rita
AU - Liu, Bolin
AU - Fodstad, Oystein
AU - Chen, Jieqing
AU - Wu, Yun
AU - Price, Janet E.
AU - Tan, Ming
PY - 2011/7/1
Y1 - 2011/7/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-11-0127
DO - 10.1158/0008-5472.CAN-11-0127
M3 - Article
C2 - 21498634
AN - SCOPUS:79959861423
SN - 0008-5472
VL - 71
SP - 4585
EP - 4597
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -