Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism.
Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism.
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DOI：
10.1158/0008-5472.can-11-0127
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发表时间：
2011-07-01
期刊：
影响因子：
11.2
通讯作者：
Tan M
中科院分区：
文献类型：
--
作者：
Zhao Y;Liu H;Liu Z;Ding Y;Ledoux SP;Wilson GL;Voellmy R;Lin Y;Lin W;Nahta R;Liu B;Fodstad O;Chen J;Wu Y;Price JE;Tan M
曲妥珠单抗在单独使用或与其他化疗药物联合使用时，在治疗ErbB 2阳性乳腺癌方面显示出显著的疗效。然而，获得性耐药性在大多数接受治疗的患者中发展，需要替代治疗策略。有氧糖酵解增加是癌症的标志，抑制糖酵解可能提供优先杀死癌细胞的有希望的策略。在这项研究中，我们研究了曲妥珠单抗联合糖酵解抑制剂在ErbB 2阳性乳腺癌中的抗肿瘤作用。我们发现曲妥珠单抗通过下调ErbB 2阳性癌细胞中的热休克因子1（HSF 1）和乳酸脱氢酶A（LDH-A）抑制糖酵解，从而抑制肿瘤生长。此外，通过HSF 1和LDH-A增加的糖酵解有助于曲妥珠单抗耐药性。重要的是，我们发现，曲妥珠单抗与糖酵解抑制相结合，在体外和体内协同抑制曲妥珠单抗敏感和耐药乳腺癌，由于更有效地抑制糖酵解。综上所述，我们的研究结果显示了糖酵解抑制如何显著增强曲妥珠单抗在ErbB 2阳性乳腺癌中的治疗效果，这可能有助于克服曲妥珠单抗耐药性。
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.