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

Abstract

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.