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Mitotic Checkpoint Kinase Mps1 Has a Role in Normal Physiology which Impacts Clinical Utility
Ricardo Martinez1, Alessandra Blasina1, Jill F Hallin1
1Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
Plos One
|September 24, 2015
Summary
Targeting the mitotic checkpoint kinase Mps1 shows promise for cancer therapy, particularly in triple-negative breast cancer. However, Mps1 inhibitors cause toxicity, suggesting combination therapy with CDK4/6 inhibitors may improve tolerability.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Cell cycle checkpoint intervention is a key cancer therapeutic strategy.
- The mitotic checkpoint (spindle assembly checkpoint) regulates chromosome segregation and is a potential therapeutic target.
- Mps1 kinase is upregulated in basal-a triple-negative breast cancer, a model system with high genomic instability.
Purpose of the Study:
- To investigate Mps1 kinase as a therapeutic target by exploring the consequences of its inhibition on tumor cells and normal physiology.
- To assess the therapeutic potential of potent Mps1 inhibitors (PF-7006, PF-3837) in triple-negative breast cancer models.
- To evaluate strategies for mitigating Mps1 inhibitor toxicities.
Main Methods:
- Developed highly selective Mps1 kinase inhibitors (PF-7006, PF-3837) with nanomolar potency.
- Treated triple-negative breast cancer cells in vitro and tumor-bearing mice with PF-7006.
- Assessed molecular and phenotypic changes, including pHH3-Ser10 levels, mitosis duration, and apoptosis.
- Utilized an isogenic cellular model to evaluate Rb1-deficiency and Rb1-competency.
- Investigated the combination of Mps1 inhibitors with cyclin-dependent kinase-4/6 (CDK4/6) inhibitors (palbociclib) to mitigate toxicity.
Main Results:
- Mps1 depletion reduced tumor cell viability.
- PF-7006 treatment modulated Mps1-dependent pathways in vitro, leading to reduced pHH3-Ser10, shorter mitosis, micro-nucleation, and apoptosis.
- PF-7006 inhibited tumor growth in mice, with pharmacodynamic evidence of target engagement.
- Mps1 inhibition caused dose-limiting toxicities including weight loss, gastrointestinal issues, and neutropenia.
- PF-7006 demonstrated selective cytotoxicity towards Rb1-deficient cells.
- Pretreatment with palbociclib reduced PF-7006-induced apoptosis in human bone marrow cells.
Conclusions:
- Single-agent Mps1 inhibition may not be clinically well-tolerated due to dose-limiting toxicities.
- Combination therapy with CDK4/6 inhibitors may offer a strategy to mitigate Mps1 inhibitor toxicities and improve clinical tolerability.
- Targeting Mps1 remains a promising avenue for cancer therapy, especially when combined with agents that modulate cell cycle arrest.
