Abstract
BackgroundTrastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. However, recurrent therapeutic resistance presents revolutionary claims. Warburg effect and AKT signaling pathway was involved in the resistance to trastuzumab. Our previous studies have demonstrated that overexpression of metastasis associated with the colon cancer 1 (MACC1) predicted poor prognosis of GC and promoted tumor cells proliferation and invasion. In this study, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 reversed this resistance.MethodsThe effect of trastuzumab and glycolysis inhibitor combination on cell viability, apoptosis, and cell metabolism was investigated in vitro using established trastuzumab-resistant GC cell lines. We assessed the impact of trastuzumab combined with oxamate on tumor growth and metabolism in an established xenograft model of HER2-positive GC cell lines.ResultsHere, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 in trastuzumab-resistant cells reversed this resistance. Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effects of MACC1 on resistance and glycolysis were diminished. Our findings indicated that MACC1 promoted the Warburg effect mainly through the PI3K/AKT signaling pathway, which further enhanced GC cells trastuzumab resistance.ConclusionsOur results indicate that co-targeting of HER2 and the Warburg effect reversed trastuzumab resistance in vitro and in vivo, suggesting that the combination might overcome trastuzumab resistance in MACC1-overexpressed, HER2-positive GC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0302-1) contains supplementary material, which is available to authorized users.
Highlights
Trastuzumab, a humanized antibody targeting Human epidermal growth factor receptor 2 (HER2), exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer
We recently found that activation of the PI3K/AKT signaling pathway can leading to resistance of HER2-positive gastric cancer (GC) cells to trastuzumab [18]
metastasis associated with the colon cancer 1 (MACC1) contributed to the resistance of HER2-positive GC cells in response to trastuzumab In a previous study, we employed human gastric carcinoma cell line NCI-N87 with high HER2 expressions to generate trastuzumab-resistant NCI-N87/TR cell lines via stepwise exposure to increasing doses of trastuzumab [18]
Summary
Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. Warburg effect and AKT signaling pathway was involved in the resistance to trastuzumab. Our previous studies have demonstrated that overexpression of metastasis associated with the colon cancer 1 (MACC1) predicted poor prognosis of GC and promoted tumor cells proliferation and invasion. We found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Human epidermal growth factor receptor 2 (HER2) is a member of the receptor family associated with tumor cell proliferation, adhesion, migration, and differentiation. For HER2-positive advanced gastric cancer (GC) patients, combining chemotherapy with trastuzumab is significantly superior to chemotherapy alone with regard to efficacy and safety [3, 4]. More effective predictors of trastuzumab response in HER2-positive cancer, except for HER2, are required for personalized clinical treatment
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