Cell cycle checkpoint intervention is an effective therapeutic strategy for
cancer when applied to patients predisposed to respond and the treatment is well-tolerated. A critical cell cycle process that could be targeted is the mitotic checkpoint (spindle assembly checkpoint) which governs the metaphase-to-anaphase transition and insures proper chromosomal segregation. The mitotic checkpoint
kinase Mps1 was selected to explore whether enhancement in
genomic instability is a viable therapeutic strategy. The basal-a subset of
triple-negative breast cancer was chosen as a model system because it has a higher incidence of
chromosomal instability and Mps1 expression is up-regulated. Depletion of Mps1 reduces
tumor cell viability relative to normal cells. Highly selective, extremely potent Mps1
kinase inhibitors were created to investigate the roles of Mps1 catalytic activity in
tumor cells and normal physiology (PF-7006, PF-3837; Ki<0.5 nM; cellular IC50 2-6 nM). Treatment of
tumor cells in vitro with PF-7006 modulates expected Mps1-dependent biology as demonstrated by molecular and phenotypic measures (reduced pHH3-Ser10 levels, shorter duration of mitosis, micro-nucleation, and apoptosis).
Tumor-bearing mice treated with PF-7006 exhibit
tumor growth inhibition concomitant with pharmacodynamic modulation of a downstream
biomarker (pHH3-Ser10). Unfortunately, efficacy only occurs at
drug exposures that cause dose-limiting
body weight loss, gastrointestinal toxicities, and
neutropenia. Mps1 inhibitor toxicities may be mitigated by inducing G1 cell cycle arrest in Rb1-competent cells with the
cyclin-dependent kinase-4/6 inhibitor
palbociclib. Using an isogenic cellular model system, PF-7006 is shown to be selectively cytotoxic to Rb1-deficient cells relative to Rb1-competent cells (also a measure of
kinase selectivity). Human bone marrow cells pretreated with
palbociclib have decreased PF-7006-dependent apoptosis relative to cells without
palbociclib pretreatment. Collectively, this study raises a concern that single agent
therapies inhibiting Mps1 will not be well-tolerated clinically but may be when combined with a selective CDK4/6
drug.