Open AccessCDK 4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib
Author(s) -
Raspé Eric,
Coulonval Katia,
Pita Jaime M,
Paternot Sabine,
Rothé Françoise,
Twyffels Laure,
Brohée Sylvain,
Craciun Ligia,
Larsimont Denis,
Kruys Véronique,
Sandras Flavienne,
Salmon Isabelle,
Van Laere Steven,
Piccart Martine,
Ignatiadis Michail,
Sotiriou Christos,
Roger Pierre P
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201607084
Subject(s) - cyclin dependent kinase , palbociclib , cdk inhibitor , cyclin dependent kinase 6 , phosphorylation , cell cycle , cancer research , biology , restriction point , gene expression , breast cancer , kinase , cyclin , gene , microbiology and biotechnology , cancer , genetics , metastatic breast cancer
Cyclin D‐ CDK 4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK 4/6 inhibitor PD 0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER ‐positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK 4 is the central rate‐limiting event that initiates the cell cycle decision and signals the presence of active CDK 4. Here, we report that the profile of post‐translational modification including T172 phosphorylation of CDK 4 differs among breast tumors and associates with their subtypes and risk. A gene expression signature faithfully predicted CDK 4 modification profiles in tumors and cell lines. Moreover, in breast cancer cell lines, the CDK 4 T172 phosphorylation best correlated with sensitivity to PD 0332991. This gene expression signature identifies tumors that are unlikely to respond to CDK 4/6 inhibitors and could help to select a subset of patients with HER 2‐positive and basal‐like tumors for clinical studies on this class of drugs.