Abstract
Abstract Treatment of cells with the BH3 domain/MCL-1 inhibitor obatoclax enhanced the lethality of lapatinib in a synergistic fashion in multiple tumor cell types, including ER+; HER2+; triple negative breast cancer cells and glioblastoma and medulloblastoma cells. Knock out of MCL-1 and BCL-XL enhanced lapatinib toxicity to a similar extent as obatoclax and suppressed the ability of obatoclax to promote lapatinib lethality. Pre-treatment of cells with lapatinib or with obatoclax enhanced basal levels of BAX and BAK activity and further enhanced drug combination toxicity. In vitro, treatment of breast cancer cells with obatoclax and lapatinib enhanced the toxicity of ionizing radiation. In vivo tumor growth data in xenograft and syngeneic model systems of breast cancer confirmed our in vitro findings. Lapatinib and obatoclax interacted to suppress mammary tumor growth in vivo without causing toxicity to multiple normal tissues including brain, heart, lungs, liver or kidneys. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5383. doi:10.1158/1538-7445.AM2011-5383
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