Abstract 4685: Metformin enhances trastuzumab efficacy for HER2+ gastric cancer cells

Background: Trastuzumab is an effective monoclonal antibody against advanced gastric cancers (GCs) with HER2 amplification. Recently, HER2 directed therapies, such as pertuzumab or lapatinib are actively investigated in clinical trials, but showed disappointing results in patients with HER2+ GC. Unfortunately, the efficacy of trastuzumab is limited due to primary and acquired resistance to this agent. Metformin is a widely used antidiabetic drug and shows promising anti-tumor effect in several cancers. Material and Methods: The following GC cells were evaluated: HER2 amplification -positive (HER2+) and trastuzumab-sensitive NCI-N87 and OE19, HER2+ trastuzumab-resistant OE33 and HER2 negative AGS, H1750 and SNU601. We assessed response of these GC cells to trastuzumab alone or in combination with metformin by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and anchorage independent growth in soft agar. MGI (mean growth inhibition) was calculated by dividing the colony number of the treated group by that of the untreated control group. Western blots were performed to assess biochemical changes, especially those related with HER2 signaling components. Results: We observed that treatment with trastuzumab in combination with metformin induced a statistically significant decrease in the number of colonies formed in soft agar by N87 and OE19 cells, as compared to the numbers formed by control cells or cells in the single-treatment groups (Kruskal-Wallis test, p = 0.025, respectively). No growth inhibitory effect was detected in OE33 cells with Compared to trastuzumab alone, the combination of metformin resulted in decreased phosphorylation of HER2 and downstream targets, such as AKT or ERK, in trastuzumab-sensitive HER2+ cells. Conclusion: Collectively, these data support that trastuzumab and metformin are synergistic in trastuzumab-sensitive HER2+ GC cells. Citation Format: Jin-Soo Kim, Geum Ock Kim, Mi Young Kim. Metformin enhances trastuzumab efficacy for HER2+ gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4685.