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Review
. 2023 Jan 19:13:1095219.
doi: 10.3389/fonc.2023.1095219. eCollection 2023.

Targeting cyclin-dependent kinases in sarcoma treatment: Current perspectives and future directions

Alessandra Merlini  1   2 , Valeria Pavese  2 , Giulia Manessi  2 , Martina Rabino  2 , Francesco Tolomeo  1 , Sandra Aliberti  1 , Lorenzo D'Ambrosio  2   3 , Giovanni Grignani  1
Affiliations
Review

Targeting cyclin-dependent kinases in sarcoma treatment: Current perspectives and future directions

Alessandra Merlini et al. Front Oncol. .

Abstract

Effective treatment of advanced/metastatic bone and soft tissue sarcomas still represents an unmet medical need. Recent advances in targeted therapies have highlighted the potential of cyclin-dependent kinases (CDK) inhibitors in several cancer types, including sarcomas. CDKs are master regulators of the cell cycle; their dysregulation is listed among the "hallmarks of cancer" and sarcomas are no exception to the rule. In this review, we report both the molecular basis, and the potential therapeutic implications for the use of CDK inhibitors in sarcoma treatment. What is more, we describe and discuss the possibility and biological rationale for combination therapies with conventional treatments, target therapy and immunotherapy, highlighting potential avenues for future research to integrate CDK inhibition in sarcoma treatment.

Keywords: cdk inhibitors; cell cycle; cyclin dependent kinases (CDK); sarcoma; target therapy.

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Conflict of interest statement

AM: travel expenses from PharmaMar. LA received travel expenses from PharmaMar and Lilly. GG has received fees for consulting and advisory board roles from PharmaMar, Lilly, Novartis, GSK, Bayer, and Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Key players in cell cycle dysregulation in STS. CDK, Cyclins, CKI, and other key molecular players in CDK activity/inhibition. Clockwise, starting from G1 to S phase progression: CDKN2A is transcribed by alternative splicing either into p16 or p14, which respectively inhibit CDK4/6/Cyclin D complexes and MDM2 activity. MDM2, an ubiquitin ligase, ubiquitinates p53 targeting it to the proteasome; p53 has p21 as a direct transcriptional target, and p21 in turn inhibits CDK2/Cyclin E complexes. Cyclin E expression is regulated by E2F transcription factor, which in turn is released from Rb protein grip (usually blocking its transactivation domain) when CDK4/6/Cyclin D complexes phosphorylate Rb, facilitating G1 to S phase progression. The ubiquitin ligase Skp2 targets p21 and p27 for proteasomal degradation, thus promoting CDK2/Cyclin E, CDK2/Cyclin A activity in S phase progression, CDK1/Cyclin A activity for G2 to M transition, which is also fostered by releasing p21 inhibitory activity on CDK1/Cyclin B; DUX4 can also bind CDK1, thus preventing CDK1/Cyclin B interaction. MDM2 activity can also be inhibited with MDM2 inhibitors (MDM2i), while CDK inhibitors (CDKi) currently in use in clinical practice are mainly CDK4/6 inhibitors. MDM2i and CDKi are highlighted in bold (red) in Figure 1 . Created with BioRender.com .
See this image and copyright information in PMC

References

    1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin (2022) 72:7–33. doi: 10.3322/caac.21708 - DOI - PubMed
    1. WHO Classification of Tumours Editorial Board . Soft tissue and bone tumours. ed. 5th Vol. vol. 3. . Lyon (France: WHO classification of tumours series (International Agency for Research on Cancer; (2020).
    1. Gronchi A, Miah AB, Dei Tos AP, Abecassis N, Bajpai J, Bauer S, et al. . Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol (2021) 32:1348–65. doi: 10.1016/j.annonc.2021.07.006 - DOI - PubMed
    1. Lochner J, Menge F, Vassos N, Hohenberger P, Kasper B. Prognosis of patients with metastatic soft tissue sarcoma: Advances in recent years. Oncol Res Treat (2020) 43:613–9. doi: 10.1159/000509519 - DOI - PubMed
    1. Hall F, Villalobos V, Wilky B. Future directions in soft tissue sarcoma treatment. Curr Probl Cancer (2019) 43:300–7. doi: 10.1016/j.currproblcancer.2019.06.004 - DOI - PubMed