Dual Inhibition of CDK4 and CDK2 via Targeting p27 Tyrosine Phosphorylation Induces a Potent and Durable Response in Breast Cancer Cells.

ABSTRACT: Cyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4. p27Kip1 is a required assembly factor for cyclin-CDK4 complexes, but it must be phosphorylated on residue Y88 to open or activate the complex. The Brk-SH

SUBMITTER: Patel P 

PROVIDER: S-EPMC5835198 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature