Journal Article

The history and future of targeting cyclin-dependent kinases in cancer therapy

Turner, Nicholas C., Asghar, Uzma, Witkiewicz, Agnieszka K., Knudsen, Erik S.

2015

Overview

Key Points Cyclin-dependant kinase 4 (CDK4) and CDK6 phosphorylate the tumour suppressor retinoblastoma protein (RB), resulting in the release of the E2F transcription factor and progression through the cell cycle. CDK4 and CDK6 are positively regulated by D-type cyclins (that is, cyclin D1, cyclin D2 and cyclin D3) and negatively regulated by inhibitor of CDK4 (INK4) proteins. In cancer, the CDK4/CDK6–RB–p16 INK4A pathway is dysregulated through various mechanisms, including loss of p16 INK4A , loss of RB, overexpression of cyclin D1 or of CDK4 and CDK6. Clinical trials with pan-CDK inhibitors, such as flavopiridol, have demonstrated low levels of clinical activity and drug target selectivity. The reasons for their failure in the clinic include the absence of clear biomarkers for response and the lack of a clear therapeutic window. The selective CDK4 and CDK6 inhibitors palbociclib, LEE011 and abemaciclib induce G1 cell cycle arrest both in vitro and in vivo in RB-proficient models. Preclinical activity has been reported in multiple tumour types, including breast cancer, sarcoma, melanoma and mantle cell lymphoma. The PALOMA-1 Phase II clinical trial randomized 165 women with advanced oestrogen receptor (ER)-positive breast cancer into two treatment groups: the aromatase inhibitor letrozole alone versus letrozole plus palbociclib. There was a significant improvement of 10 months in median progression-free survival with letrozole plus palbociclib compared with letrozole alone Neutropaenia is the principal drug-limiting toxicity for the selective CDK4 and CDK6 inhibitors palbociclib and LEE011. Abemaciclib has demonstrated more prominent gastrointestinal-associated toxicity. Loss of RB and higher levels of p16 INK4A are markers of resistance to selective CDK4 and CDK6 inhibitors. Further evaluation of predictive biomarkers across tumour types is required. Components of the cell cycle machinery, such as the cyclin-dependent kinases (CDKs), have long been pursued as anticancer targets. Historically, the development of CDK inhibitors has been challenging, but recent developments, particularly in regard to inhibitors for CDK4 and CDK6, have shown promise. This Review presents an overview of the field and discusses agents in clinical development. Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1059/153 / 631/92/612/1223 / 692/699/67 / Animals / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biomedicine / Biotechnology / Cancer / Cancer Research / Care and treatment / Cell Cycle - drug effects / Clinical Trials as Topic / Cyclin-Dependent Kinases - antagonists & inhibitors / Cyclin-Dependent Kinases - genetics / Cyclin-Dependent Kinases - metabolism / Drug Discovery / Drug Evaluation, Preclinical / Drug targeting / Gene Expression Regulation, Neoplastic - drug effects / Health aspects / Humans / Medicinal Chemistry / Molecular Medicine / Molecular Structure / Molecular Targeted Therapy - methods / Molecular Targeted Therapy - trends / Neoplasms - drug therapy / Neoplasms - enzymology / Neoplasms - pathology / Oncology, Experimental / Pharmacology, Experimental / Pharmacology/Toxicology / Phosphotransferases / review-article / Signal Transduction - drug effects