title: Modeling the mitotic regulatory network identifies highly efficient anti-cancer drug combinations.
abstract: Targeting mitotic regulation is recognized as an important strategy for cancer therapy. Aurora A/B kinase and polo-like kinase 1 (PLK1) are the key mitotic regulators, and many inhibitors have been developed. Combinations of these inhibitors are anticipated to be more effective therapeutics compared with single-inhibitor treatments; however, a systematic analysis of the combined effects is lacking. Here, we constructed the first mammalian cell mitotic regulation network model, which spans from mitotic entry to anaphase initiation, and contains all key mitotic kinase targets. The combined effects of different kinase inhibitors and microtubule inhibitors were systematically explored. Simultaneous inhibition of Aurora B and PLK1 strongly induces polyploidy. Microtubule inhibitor dosage can be significantly reduced when combined with a PLK1 inhibitor. The efficacy of these inhibitor combinations was validated by our experimental results. The mitotic regulatory network model provides a platform to study the complex interactions during mitosis, enables identification of mitotic regulators, and determines targets for drug discovery research. The suggested use of combining microtubule inhibitors with PLK1 inhibitors is anticipated to enhance microtubule-inhibitor tolerance in a wide range of patients.
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, and Peking-Tsinghua Center for Life Sciences at College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. lhlai@pku.edu.cn.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhuo
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Dai
authors.forename: Xiao
authors.initials: X
authors.lastname: Guo
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Chuanmao
authors.initials: C
authors.lastname: Zhang
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003198:Computer Simulation; D053263:Gene Regulatory Networks / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis; D008954:Models, Biological; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015203:Reproducibility of Results; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1