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Treating cancer with selective CDK4/6 inhibitors

Key Points

  • The actions of cyclin-dependent kinases (CDK) 4/6, through phosphorylation of retinoblastoma-associated protein 1 (RB1) are pivotal in the transition from G1 to S phase in many cancer cells

  • The effectiveness of non-selective inhibition of CDKs is hampered by toxicities, selective CDK4/6 inhibition results in fewer toxicities and also provides promising antitumour effectiveness in various tumour types

  • Evidence of antitumour activity from phase III trials is currently available for palbociclib in patients with hormone-receptor (HR) positive metastatic breast cancer that have progressed on prior endocrine therapy

  • CDK4/6 inhibitors are most effective in combination with endocrine therapy in patients with HR-positive breast cancer: preclinical data support the combination of CDK4/6 inhibitors with PI3K and/or MAPK inhibitors

  • Loss of RB1 function is an established mechanism of primary resistance to CDK4/6 inhibitors in vitro, but this, and other biomarkers are yet to be validated clinically

Abstract

Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.

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Figure 1: Classical and non-classical models of the cell cycle in RB1-proficient cells.
Figure 2: Chemical structure of selective CDK4/6 inhibitors.
Figure 3: The cell cycle and the role of CDK4/6 inhibition.
Figure 4: Possible combination therapies CDK4/6 inhibitors.

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Acknowledgements

We acknowledge funding from the UK NHS to the Royal Marsden NIHR Biomedical Research Centre.

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N.C.T. is a member of the advisory boards of Lilly, Novartis and Pfizer. R.S.F. declares that he has acted as an advisor for Bayer Pharmaceuticals, Bristol–Myers Squibb, Novartis, and Pfizer, and has received research support from these companies via his institution. B.O. declares no competing interests.

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O'Leary, B., Finn, R. & Turner, N. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 13, 417–430 (2016). https://doi.org/10.1038/nrclinonc.2016.26

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