BioProject

Cyclin D-CDK4/6 are the first CDK complexes to be activated in G1 phase in response to oncogenic pathways. More...

Cyclin D-CDK4/6 are the first CDK complexes to be activated in G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (Palbociclib) was recently approved by the FDA to treat advanced ER+ breast tumors. Unfortunately, reliable predictive tools are lacking to identify potentially responsive or insensitive tumors. We have shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we found that, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlates with the sensitivity to PD0332991. Moreover, the modification profile of CDK4 differs among breast tumors and it associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. This surrogate biomarker identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could allow extending the indication of the drug to HER-2 positive and some basal-like tumors. Predictive tools to identify breast cancer patients sensitive to Pfizer's new drug targeting CDK4/6 are lacking. We correlated the sensitivity of breast cancer cell lines to the drug to their post-translational modification profile of CDK4 revealed by 2D SDS/poly-acrylamide gel electrophoresis followed by CDK4 immuno-detection and their gene expression profiles. we revealed that breast tumors display similar CDK4 post-translational modification profiles as cell lines and that a gene expression profile can be used to predict the CDK4 post-translational modification profile of a tumor or cell line and thereby its sensitivity to CDK4 inhibitor Overall design: 20 breast cell lines (10 basal, 7 HER2+, 3 Lum) were acquired at the ATCC. RNA was profiled using the Affymetrix HG-U133 Plus 2.0 chips while protein extracts were resolved by 2D SDS-PAGE and probed with anti CDK4 antibody. Gene expression profiles were compared to proteomic profiles to associate the CDK4 modification status to gene expression levels. The Affymetrix microarray data were normalized using fRMA. This submission represents the gene expression component of the study only. No replicate, no reference sample. Less...