Abstract 4036: Induction of detrimental aneuploidy in basal breast cancer cells treated by MPS1 inhibitors in combination with paclitaxel

Abstract

Abstract Basal-like breast cancer has received considerable attention in recent years, but despite all efforts, conventional chemotherapy remains the main therapeutic option in the clinic with taxane therapy, the most frequently prescribed treatment. A significant reason for the lack of effective therapeutics may be related to the high degree of heterogeneity and aneuploidy which is characteristic for basal-like breast cancer. A new approach in this field is the concept that cancer cells may be targeted by the introduction of a detrimental level of aneuploidy. Inhibition of one of the main spindle assembly checkpoint kinases, MPS1 is a rational choice to achieve this goal. We report here the identification of a synergistic effect between the novel, oral, highly potent and selective MPS1 inhibitor CCT289346 and paclitaxel. We demonstrate robust synergism in multiple basal-like breast cancer cell lines and provide mechanistic insights into how both compounds’ individual properties work together to maximise mitotic defects thereby increasing aneuploidy and cell death in a single round of mitosis. Additionally, in vivo studies in basal-like breast cancer xenograft models, including patient derived xenografts and systemic metastatic models, using clinically relevant doses of paclitaxel with well-tolerated doses of CCT289346, demonstrate significant benefit of combination of the two agents in comparison to paclitaxel alone. Citation Format: Simon J. Anderhub, Grace WY Mak, Amir Faisal, Katie Walsh, Mark Gurden, Liz Day, Paolo Innocenti, Hannah L. Woodward, Isaac M. Westwood, Kwai-Ming J. Cheung, Sebastien Naud, Angela Hayes, Gary Box, Alexis de Haven Brandon, Melanie R. Valenti, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob LM van Montfort, Florence I. Raynaud, Suzanne A. Eccles, Julian Blagg, Swen Hoelder, Spiros Linardopoulos. Induction of detrimental aneuploidy in basal breast cancer cells treated by MPS1 inhibitors in combination with paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4036. doi:10.1158/1538-7445.AM2017-4036