Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Oct 10;15(20):4923.
doi: 10.3390/cancers15204923.

The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition

Graziana Scavone  1 , Silvia Ottonello  1 , Eva Blondeaux  2 , Luca Arecco  1   3 , Paola Scaruffi  4 , Sara Stigliani  4 , Barbara Cardinali  1 , Roberto Borea  1   3 , Michele Paudice  5 , Valerio G Vellone  5   6 , Margherita Condorelli  7   8 , Isabelle Demeestere  7   8 , Matteo Lambertini  1   3
Affiliations
Review

The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition

Graziana Scavone et al. Cancers (Basel). .

Abstract

The combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy is the standard treatment for patients with HR+/HER2- advanced breast cancer. Recently, this combination has also entered the early setting as an adjuvant treatment in patients with HR+/HER2- disease at a high risk of disease recurrence following (neo)adjuvant chemotherapy. Despite their current use in clinical practice, limited data on the potential gonadotoxicity of CDK4/6 inhibitors are available. Hence, fully informed treatment decision making by premenopausal patients concerned about the potential development of premature ovarian insufficiency and infertility with the proposed therapy remains difficult. The cell cycle progression of granulosa and cumulus cells is a critical process for ovarian function, especially for ensuring proper follicular growth and acquiring competence. Due to the pharmacological properties of CDK4/6 inhibitors, there could be a potentially negative impact on ovarian function and fertility in women of reproductive age. This review aims to summarize the role of the cyclin D-CDK4 and CDK6 complexes in the ovary and the potential impact of CDK4/6 inhibition on its physiological processes.

Keywords: CDK 4/6 inhibitors; cyclin D-CDK 4/6 complex; gonadotoxicity; ovary.

PubMed Disclaimer

Conflict of interest statement

Matteo Lambertini reports his advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo and Takeda; travel grants from Gilead and Daiichi Sankyo; and research support (to the Institution) from Gilead outside the submitted work. Eva Blondeaux reports research support (to the Institution) from Gilead outside the submitted work. All the other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
CDK 4/6 complex activation allows entry into G1 phase and cell cycle progression. Created by the authors using BioRender.com, accessed on 22 April 2023.
Figure 2
Figure 2
RB phosphorylation leads to the transcription of pro-proliferative genes. Created by the authors using BioRender.com, accessed on 22 April 2023.
Figure 3
Figure 3
The INK-4 family and the CIP/KIP-type family inhibit the cyclin D-CDK4/6 complex and cyclin A/E-CDK1, CDK2, CDK4 and CDK6, respectively. On the one hand, these complexes’ inactivation leads to a state of cell quiescence in the G0 phase, and on the other, it prevents transition to the S phase. Created by the authors using BioRender.com, accessed on 22 April 2023.
Figure 4
Figure 4
Primordial follicles are in a quiescence state as a result of SMAD3 activation by TGFβ factor. However, when SMAD3 is inactive, progression in growing follicles is enabled. Created by the authors using BioRender.com, accessed on 22 April 2023.
See this image and copyright information in PMC

References

    1. Siegel R.L., Miller K.D., Wagle N.S., Jemal A. Cancer Statistics, 2023. CA Cancer J. Clin. 2023;73:17–48. doi: 10.3322/caac.21763. - DOI - PubMed
    1. Paluch-Shimon S., Cardoso F., Partridge A.H., Abulkhair O., Azim H.A., Bianchi-Micheli G., Cardoso M.J., Curigliano G., Gelmon K.A., Gentilini O., et al. ESO-ESMO Fifth International Consensus Guidelines for Breast Cancer in Young Women (BCY5) Ann. Oncol. 2022;33:1097–1118. doi: 10.1016/j.annonc.2022.07.007. - DOI - PubMed
    1. Lambertini M., Peccatori F.A., Demeestere I., Amant F., Wyns C., Stukenborg J.-B., Paluch-Shimon S., Halaska M.J., Uzan C., Meissner J., et al. Fertility Preservation and Post-Treatment Pregnancies in Post-Pubertal Cancer Patients: ESMO Clinical Practice Guidelines. Ann. Oncol. 2020;31:1664–1678. doi: 10.1016/j.annonc.2020.09.006. - DOI - PubMed
    1. Yildiz S., Bildik G., Benlioglu C., Turan V., Dilege E., Ozel M., Kim S., Oktem O. Breast Cancer Treatment and Ovarian Function. Reprod. BioMed. Online. 2023;46:313–331. doi: 10.1016/j.rbmo.2022.09.014. - DOI - PubMed
    1. Oktem O., Oktay K. A Novel Ovarian Xenografting Model to Characterize the Impact of Chemotherapy Agents on Human Primordial Follicle Reserve. Cancer Res. 2007;67:10159–10162. doi: 10.1158/0008-5472.CAN-07-2042. - DOI - PubMed