Abstract
Abstract [Background] Overexpression of human epidermal growth factor receptor 2 (HER2) was observed in approximately 20%-25% of breast cancers and they are classified in HER2-positive breast cancer. Trastuzumab is a therapeutic drug for the first choice for HER2-positive breast cancer, showing good response. However, acquired resistance to trastuzumab is one of the critical clinical issues in breast cancer treatment, especially in the patients with recurrent breast cancer. Therefore it is necessary to develop the effective therapy to overcome resistance. In this study, we established a trastuzumab-resistant breast cancer cell line from a trastumab-sensitive cell line with HER2 amplification (BT-474), and demonstrated anti-tumor effect of dasatinib in the breast cancer cell with trastuzumab resistance. [Methods] Trastuzumab-resistant breast cancer cell line (BT-474-R) was established by treating BT-474 cells for long-term exposing with trastuzumab. We performed cell viability assay to analyze drug sensitivity. Then, we performed quantitative PCR and western blotting to investigate expression and activation of HER2 and related molecules. Cell viability assay and signal analysis were performed with or without trastuzumab and/or dasatinib treatment. [Results] Proto-oncogene tyrosine-protein kinase Src was up-regulated and activated in BT-474-R. Signaling molecules, such as Akt and MAPK, were also activated. Dasatinib, which is known as a Src inhibitor, suppressed the activation of signal molecules and cell survival of BT-474-R. Moreover, dasatinib treatment recovered sensitivity to trastumab in the BT-474-R with down-regulation of Src phosphorylation. [Conclusion] Src plays an important role in acquired resistance to trastumab in breast cancer. Our data also suggest that inhibition of Src may become the new strategy to overcome trastuzumab resistance. Citation Format: Tatsuaki Takeda, Hirotaka Kanzaki, Shinichi Toyooka, Mototsugu Watanabe, Tomoaki Ohtsuka, Ken Suzawa, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo. Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 724. doi:10.1158/1538-7445.AM2015-724
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