title: Mitotic Checkpoint Kinase Mps1 Has a Role in Normal Physiology which Impacts Clinical Utility.
abstract: 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.
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Blasina
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Jill F
authors.initials: JF
authors.lastname: Hallin
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Isha
authors.initials: I
authors.lastname: Rymer
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Fan
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hoffman
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Murphy
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Marx
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Gina
authors.initials: G
authors.lastname: Yanochko
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Dusko
authors.initials: D
authors.lastname: Trajkovic
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Dac
authors.initials: D
authors.lastname: Dinh
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, United States of America.
authors.forename: Peiquing
authors.initials: P
authors.lastname: Sun
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Lappin
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10724 Science Center Drive, San Diego, CA, 92121, United States of America.
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D014183:Transplantation, Heterologous
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C075840:TTK protein, human; C500026:palbociclib