Investigational drugs targeting cyclin-dependent kinases for the treatment of cancer: an update on recent findings (2013-2016)

ABSTRACT

Introduction: Cell cycle and gene transcription are under the control of cyclin-dependent kinases (CDKs), whose activity depends on the binding with cyclins. Deregulated CDK activities have been reported in a majority of human cancers, representing potential therapeutic targets.

Areas covered: This review provides preclinical and clinical (phase I/II) updates of promising therapeutic compounds targeting CDKs published between 2013 and 2016

Expert opinion: First generation pan-CDK inhibitors showed marked toxicity in clinical trials and most compounds were discontinued. Despite their failure was ascribed also to inadequate patient selection rules, novel pan-CDK inhibitors have entered clinical trials with still poorly defined selection strategies. The most interesting results have been obtained with dual CDK4/6 inhibitors and through a more accurate evaluation of predictive biomarkers, suggesting the usefulness of CDK inhibitors for personalized treatment. The increased knowledge on the roles of CDKs in cell cycle and gene transcription suggests to review also the anticancer potential of first generation CDK inhibitors by defining more appropriate rules for patients engagement. Recent findings has highlighted CDK8 as a novel target for cancer treatment. Indeed some biomarkers for CDK8 inhibition sensitivity have already been proposed. CDK8 inhibition is also supposed to prevent cancer metastasis.

KEYWORDS:

• Cyclin-dependent kinases (CDKs)
• cancer
• CDK8 inhibitors
• CDK selective inhibitors
• clinical trial

Article highlights

• NCT02624973 PErsonalized TREatment of High-risk MAmmary Cancer (PETREMAC) trial is a new emerging type of study oriented to the development of the personalized medicine by the identification of the mechanisms of drug sensitivity/resistance across individual tumours

• The most promising class of cell cycle targeting agents are the dual CDK4/CDK6 inhibitors, active in the treatment of ER+/HER2- breast cancer patients with overexpression of cyclin D and inactivating mutations in p16. However, in these last years, several trials of phase I/II were opened to the aim to evaluate the efficacy and safety of the CDK4/CDK6 inhibitors in other cancer types.

• In January 2016, Palbociclib received expanded approval at the dosage of 125mg for the treatment of HR+/HER2- advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression following endocrine therapy.

• The most promising clinical results with CDK inhibitors have been obtained through the association with other known anticancer drugs, further highlighting the importance of multi-target approach

• CDK8 is an emerging oncogene involved in the modulation of the transcription. The first and most promising CDK8 inhibitors are currently in preclinical stage of development

• Preclinical data on senexin B suggested a high potential for CDK8 inhibitors in both prevention and treatment of breast cancer

This box summarizes key points contained in the paper.

Declaration of interest

C Di Giovanni discloses support from University of Napoli – Federico II, E Novellino discloses support from University of Napoli – Federico II, A Chilin discloses support from the University of Padova, A Lavecchia discloses support from University of Napoli – Federico II, and G Marzaro discloses support from the University of Padova. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work has been carried out with financial support of Università degli Studi di Padova to G Marzaro. (Progetto giovani studiosi 2012, University of Padova).