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Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma

Abstract

The treatment of advanced and metastatic kidney cancer has entered a golden era with the addition of more therapeutic options, improved survival and new targeted therapies. Tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint blockade have all been shown to be promising strategies in the treatment of renal cell carcinoma (RCC). However, little is known about the best therapeutic approach for individual patients with RCC and how to combat therapeutic resistance. Cancers, including RCC, rely on sustained replicative potential. The cyclin-dependent kinases CDK4 and CDK6 are involved in cell-cycle regulation with additional roles in metabolism, immunogenicity and antitumour immune response. Inhibitors of CDK4 and CDK6 are now commonly used as approved and investigative treatments in breast cancer, as well as several other tumours. Furthermore, CDK4/6 inhibitors have been shown to work synergistically with other kinase inhibitors, including mTOR inhibitors, as well as with immune checkpoint inhibitors in preclinical cancer models. The effect of CDK4/6 inhibitors in kidney cancer is relatively understudied compared with other cancers, but the preclinical studies available are promising. Collectively, growing evidence suggests that targeting CDK4 and CDK6 in kidney cancer, alone and in combination with current therapeutics including mTOR and immune checkpoint inhibitors, might have therapeutic benefit and should be further explored.

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Fig. 1: CDK4 stabilization and canonical function in the cell cycle.
Fig. 2: Cellular functions and regulation of CDK4.
Fig. 3: Structure of CDK6 in complex with CDK4/6 inhibitors.
Fig. 4: Timeline of CDK4/6 inhibitor development and approval of systemic therapies for renal cell carcinoma.
Fig. 5: CDK4 at the interface between mTOR signalling and immune checkpoint regulation.

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Acknowledgements

The authors are grateful to W. Marston Linehan (Urologic Oncology Branch, NCI) for his scientific contribution. This work was partly supported by the National Institute of General Medical Sciences with the NIH (grants R35GM139584, R01GM124256 and DoD KC190038 (M.M.), and R01GM139932 (D.B.)). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported by funds from SUNY Upstate Medical University and the Upstate Foundation (D.B. and M.M.).

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M.M., R.A.S., G.E.S. and I.N. researched data for article. M.M., R.A.S., S.J.B., G.B. and D.B. made substantial contribution to the discussion of content. M.M., R.A.S., S.J.B., E.A. and M.R.W. wrote the article. M.M., R.A.S. and S.J.B. reviewed/edited the manuscript before submission

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Correspondence to Mehdi Mollapour.

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Sager, R.A., Backe, S.J., Ahanin, E. et al. Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma. Nat Rev Urol 19, 305–320 (2022). https://doi.org/10.1038/s41585-022-00571-8

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