The Prospects of CDK Targeting and Clinical Application of CDK Inhibitors in Cancer
Pp. 234-286 (53)
Aditi Gangopadhyay and Aparna Gangopadhyay
CDKs (Cyclin-Dependent Kinases) are protein kinases that regulate cell
cycle progression. In cancer cells, which are characterised by unregulated proliferation,
CDK expression and activity are often deregulated. CDKs are potential therapeutic
targets in cancer therapy. However, the inhibition of CDKs is a complicated affair and
has been the subject of drug discovery for decades. With the preclinical and clinical
phases of CDK inhibitor discovery confronted by drug resistance, low selectivity, and
the need for selective inhibitors, and the successful development of CDK inhibitors is
challenging. The application of proper patient selection has shown promise in the
identification of highly selective CDK inhibitors. Promising results from clinical
studies have led to the rapid approval of CDK dual inhibitors by the FDA and EMA;
clinical guidelines from the NCCN and ESMO advocate their use in advanced breast
cancer in combination with aromatase inhibitors in hormone receptor positive patients.
Rapidly evolving data indicate that dual CDK inhibitors may favorably modulate the
immune microenvironment and thus may be good partners for checkpoint blockade.
Although promising, dual inhibitors will not offer an ultimate cure and tumour cells
will engineer a way around them. A key challenge to therapeutic application is
determining appropriate biomarkers to identify patients who may benefit most. An area
of concern, as with all targeted therapy, is the study of mechanisms of acquired
resistance to these drugs. Defining the mechanisms of resistance will be critical for
designing future strategies. The inhibition of CDKs thus presents a complicated yet
promising line of anticancer therapy. After a brief introduction to the molecular biology
of CDKs and CDK inhibition, the chapter will focus on the present status and future
prospects of targeting CDKs for cancer therapy, taking lessons from the failures and
success stories of clinical trials in CDK inhibition.
Cancer, Cell cycle, Clinical guidelines, Clinical trials, Cyclins, CDK,
CDK deregulation, CDK drug discovery, CDK inhibitors, CDK molecular
Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, West Bengal, India.