Tyrosine Phosphorylation of p27Kip1 Correlates with Palbociclib Responsiveness in Breast Cancer Tumor Cells Grown in Explant Culture.

Abstract

Cdk4-targeting drugs, such as palbociclib, are approved for metastatic ER/PR+, Her2- breast cancer. However, other than loss of retinoblastoma, which is very rare in this subset, there are no biomarkers to predict response. Cyclin D or cdk4 levels are not by themselves indicative, because p27Kip1 is required for cyclin D-cdk4 complex activation. Tyrosine phosphorylation of p27, including modification on residue Y88 (pY88), activates DK4-p27, and the pY88 level correlates with palbociclib responsiveness in cell lines. We developed dual IHC staining for p27 and pY88, and found that benign breast epithelium was negative, while breast cancer biopsies (of varied hormonal status) could be stratified for pY88 status. Lack of pY88 suggested that DK4 was inactive, and that these samples would not have the target required for palbociclib response. Tumor resection material was grown in explant culture, treated with palbociclib, and stained with Ki67 as a marker of response. Explants from the no pY88 group were nonresponsive, while explants from the low or high pY88 group responded to drug. IMPLICATIONS: Use of the pY88 biomarker, as a surrogate for cdk4 activity, may identify patients responsive to cdk4-targeting drugs and expand use of this therapy.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/3/669/F1.large.jpg.