Abstract 19: Trastuzumab resistance accompanies vasculogenic mimicry in HER2-positive breast cancer cells

Abstract

Abstract Trastuzumab (Tzm) is a drug that targets HER2/ERBB2/Neu, and is essential for the treatment of HER2-positive breast cancer. However, resistance to the drug is a major obstacle in controlling the progression of this devastating disease. We hypothesized that Tzm load might induce a phenotypic change in HER2-positive breast cancer cells, enabling them to escape and survive Tzm activity. We conducted comprehensive immunophenotyping to detect the phenotypic changes in HER2-positive breast cancer cells loaded with Tzm, and compared the immunophenotype of Tzm-loaded cells with that of control cells based on the criteria determined a priori. Out of 242 cell surface antigens, 9 antigens were significantly upregulated and 3 were significantly downregulated. Surprisingly, all the antigens were related to endothelial and stem cell phenotypes, suggesting that Tzm load induced vasculogenic mimicry (VM). Moreover, we found VM markers like COX2, MMP2, MMP14, phospho-SMAD2/3, VEGFA, HIF1A, and TWIST1 to be upregulated in Tzm-loaded cells. However, Tzm-loaded cells did not exhibit tube formation on Matrigel, a hallmark of VM. Since the Tzm-loaded cells were still sensitive to Tzm, we used three Tzm-resistant cell lines to investigate if Tzm resistance accompanied VM. All Tzm-resistant cell lines exhibited tube formation on Matrigel. Importantly, several growth factors including EGF, FGF2, IGF1, and VEGF promoted VM in these cells, suggesting that single molecular-targeted drugs did not effectively inhibit VM as other growth factors could quickly compensate the VM pathways. We then examined if eribulin, a tubulin-binding chemotherapeutic drug that promotes vascular remodeling, inhibited VM in Tzm-resistant cells. Eribulin inhibited tube formation in Tzm-resistant cells at a clinically relevant concentration. In conclusion, Tzm load induces an incomplete vasculogenic phenotype in HER2-positive breast cancer cells. The cells exhibit VM after eventually acquiring Tzm resistance. Since VM drives metastasis, its regulation in Tzm-resistant HER2-positive breast cancer appears to be a promising approach in suppressing the progression of HER2-positive breast cancer. Citation Format: Masafumi Shimoda, Ami Hori, Shinzaburo Noguchi. Trastuzumab resistance accompanies vasculogenic mimicry in HER2-positive breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 19.