LB39

MPS1 (TTK) kinase inhibition selectively kills aneuploid cells

Teeara Rawjee, Martin Rowlands, Craig McAndrew, Mark Stubbs, Christopher Lord, Jorge Reis-Filho, Alan Ashworth, Wynne Aherne, Paul Workman, Julian Blagg, Spiros Linardopoulos

The Institute of Cancer Research, London, UK

Monopolar spindle 1 (MPS1, also known as TTK) is a dual-specificity, cell cycle-regulated kinase required for the establishment and maintenance of the spindle assembly checkpoint during mitosis. Meta-analysis on expression array datasets showed increased MPS1 expression strongly correlated with time to relapse from breast cancer and this was significantly associated with breast tumours of a basal-like phenotype. However, the issue of whether inhibition of MPS1 in human tumour cells compromises their viability has not yet been fully addressed.

We show here, using an RNA interference (RNAi) approach, that inhibition of MPS1 can indeed reduce the viability of human tumour cells and that this effect is selective; aneuploid tumour cell lines are sensitive to MPS1 inhibition whereas non-cancerous cells remained resistant. To identify chemical inhibitors of MPS1, a high-throughput screen of a library of small molecules using the Homogeneous Time-Resolved Fluorescence (HTRF) assay was performed. This strategy successfully identified a hit compound that selectively reduces viability in human breast tumour cell lines. These results further validate MPS1 as a therapeutic target and identify a proof-of-principle small molecule inhibitor.