Abstract 2809: BMS-777607, a small molecule RON/MET kinase inhibitor induces polyploidy in breast cancer cells: molecular mechanism and therapeutic implication

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Aberrant RON expression contributes significantly to breast cancer tumorigenic progression. This observation has provided the basis for targeting RON in potential breast cancer treatment. In the study of breast cancer tumorigenesis, we discovered that inhibition of RON by small molecule inhibitor BMS-777607 causes polyploidy followed by apoptosis in various breast cancer cells including T-47D and ZR-75-1. BMS-777607 is a tyrosine kinase inhibitor specific to RON and MET receptor tyrosine kinases and blocks cancer cell proliferation in vitro and tumor growth in xenograft model in vivo. Using breast cancer cells as the model, we observed that BMS-777607 at experimental doses induces extensive polyploidy and apoptosis in breast cancer cells. The effect of BMS-777607 has the following features. First, BMS-777607 treatment dramatically altered cell morphology, increased cell size, and created multinucleate structures. Chromosome spreading at metaphase and flow cytometric analysis confirmed polyploid cells with 6N to 16N chromosome content, indicating that abortive mitosis and endoreduplication are responsible for the observed polyploidy. Second, the effect of BMS-777607 was highly specific and dependent on RON or MET expression. MCF-7 cells that do not express RON/MET showed only low levels of polyploidy, suggesting that RON and MET expression are required for the observed polyploid activity. Third, the effect of BMS-777607 is time and dose-dependent. A substantial polyploid population of cells accumulated within 24 h of drug treatment. Continuous cycle of abortive mitosis further increased cell ploidy with increased 16N cell fractions. Moreover, an experimental dose of 500 nM is sufficient to induce polyploidy. The maximal effect occurred when BMS-777607 was used at 5.0 μM for 72 h. Fourth, polyploidy induction promoted apoptosis and senescence of breast cancer cells, which led to significant changes in cellular sensitivity towards cytotoxic activity of chemoagents. Finally, we demonstrated that Aurora B kinase is the major signaling molecule responsible for BMS-777607-induced cancer cell polyploidy. BMS-777607 inhibited Aurora B kinase activity, which affected mitosis leading to polyploidy. In summary, BMS-777607 is a potent inducer of polyploidy in breast cancer cells. By blocking RON/MET-mediated signaling events, BMS-777607 impaired Aurora B kinase activity leading to polyploidy and apoptosis. Such observations provide mechanistic and therapeutic insight in BMS-777607 targeted cancer therapy (*supported in part by NIH grant R01 CA91980 and funds from Amarillo Area Foundation). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2809. doi:1538-7445.AM2012-2809