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Cyclers’ kinases in cell division: from molecules to cancer therapy

Cell Death & Differentiation volume 30, pages 2035–2052 (2023)Cite this article

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Abstract

Faithful eucaryotic cell division requires spatio-temporal orchestration of multiple sequential events. To ensure the dynamic nature of these molecular and morphological transitions, a swift modulation of key regulatory pathways is necessary. The molecular process that most certainly fits this description is phosphorylation, the post-translational modification provided by kinases, that is crucial to allowing the progression of the cell cycle and that culminates with the separation of two identical daughter cells. In detail, from the early stages of the interphase to the cytokinesis, each critical step of this process is tightly regulated by multiple families of kinases including the Cyclin-dependent kinases (CDKs), kinases of the Aurora, Polo, Wee1 families, and many others. While cell-cycle-related CDKs control the timing of the different phases, preventing replication machinery errors, the latter modulate the centrosome cycle and the spindle function, avoiding karyotypic abnormalities typical of chromosome instability. Such chromosomal abnormalities may result from replication stress (RS) and chromosome mis-segregation and are considered a hallmark of poor prognosis, therapeutic resistance, and metastasis in cancer patients. Here, we discuss recent advances in the understanding of how different families of kinases concur to govern cell cycle, preventing RS and mitotic infidelity. Additionally, considering the growing number of clinical trials targeting these molecules, we review to what extent and in which tumor context cell-cycle-related kinases inhibitors are worth exploiting as an effective therapeutic strategy.

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Fig. 1: Cell cycle-associated kinases inhibitors in clinical trials.
Fig. 2: Molecular overview of G1/S transition.
Fig. 3: Relevant CDKs phosphorylation targets throughout cell cycle.
Fig. 4: Cell cycle-associated kinases activity waves and their related tumors.

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Funding

Funding

GM is/has been supported by AIRC Fellowship (Ref. 26727) and by the Danish Cancer Society (R302-A17590). FC labs are supported by AIRC IG23543, Novo Nordisk 0070834, KBVU R231-A14034 and R325-A19075, PRIN 2017FS5SHL and 2020PKLEPN from the Italian Ministry of Research, RF-2019-12369700 from the Italian Ministry of Health, and Danmarks Grundforskningsfond (DNRF125).

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  1. Valeria Colicchia

    Present address: IRBM S.p.A., Via Pontina Km 30.60, 00070, Pomezia, Italy

  2. These authors contributed equally: Giacomo Milletti, Valeria Colicchia.

Authors and Affiliations

  1. DNA Replication and Cancer Group, Danish Cancer Institute, 2100, Copenhagen, Denmark

    Giacomo Milletti

  2. Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

    Giacomo Milletti

  3. Department of Biology, University of Rome Tor Vergata, Rome, Italy

    Valeria Colicchia

  4. Cell Stress and Survival Group, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Institute, Copenhagen, Denmark

    Francesco Cecconi

  5. Università Cattolica del Sacro Cuore and Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Francesco Cecconi

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GM, VC and FC conceived and conceptualized the work, GM and VC wrote the manuscript and FC edited it.

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Milletti, G., Colicchia, V. & Cecconi, F. Cyclers’ kinases in cell division: from molecules to cancer therapy. Cell Death Differ 30, 2035–2052 (2023). https://doi.org/10.1038/s41418-023-01196-z

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