34P - CDK4 phosphorylation status and corresponding gene expression profile predict sensitivity to Palbociclib.

Date 04 May 2017
Event IMPAKT 2017
Session Welcome reception and Poster Walk
Topics Breast Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Eric Raspé
Authors E. Raspé1, K. Coulonval1, J. Pita1, S. Paternot1, F. Rothé2, L. Twijffels3, S. Van Laere4, M. Ignatiadis2, C. Sotiriou2, P. Roger1
  • 1Iribhm, ULB, 1070 - Bruxelles/BE
  • 2Breast Cancer Translational Research Laboratory, Institut Jules Bordet, 1000 - Bruxelles/BE
  • 3Cmmi, Université Libre de Bruxelles, 6041 - Charleroi/BE
  • 4Core, University of Antwerp, 2610 - Wilrijk/BE



A biomarker is lacking to guide the use of the specific CDK4/6 inhibitor PD0332991 (Palbociclib) approved by the FDA to treat advanced ER+ breast tumors. Cyclin D-CDK4/6 are the first CDK complexes to be activated in G1 phase in response to oncogenic pathways. They phosphorylate and inactivate the central cell cycle/tumor suppressor pRb. They require binding to a cyclin D (CCND1-3 genes) with which CDK4 inhibitors such as p16 (CDKN2A-D genes) compete. We have shown that the activating T172-phosphorylation of CDK4 is regulated and is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4. We analyzed here the CDK4 phosphorylation in a cohort of 56 fresh-frozen breast tumor samples using 2D-gel electrophoresis. In some tumors, the phosphorylated CDK4 was undetectable as in normal breast despite a high KI67 index. In other tumors, the CDK4 phosphorylation was detectable but its intensity was either above or below 90% of the intensity of a second yet unidentified form of CDK4. The proportions of these profiles differed among breast tumors according to their clinic-pathological characteristics, molecular subtypes and risk. CDK4 phosphorylation was detectable in most Luminal B tumors but also in most HER-2 and in some basal-like tumors. The CDK4 modification profiles of breast tumors was predicted by a tool based on the expression of 11 genes. In breast cancer cell lines, T172-phosphorylated CDK4 was either undetectable or was the major modified CDK4 form. Its presence best correlated with the cell line sensitivity to PD0332991. Finally, the CDK4 modification profile prediction tool developed in the tumors also predicted the sensitivity to PD0332991 of 48 out of 52 cell lines. Patients wherein phosphorylated CDK4 is the major form should benefit the most from treatment with CDK4 inhibitors. As tumors wherein phosphorylated CDK4 is the minor form generally present low grade and risk, the drug adverse effects in these cases may exceed its clinical benefit.

Thus, we identified CDK4 phosphorylation as the most direct biomarker of CDK4 inhibitor sensitivity in breast cancer and developed a promising 11-gene based surrogate marker to guide their use in the clinic.

Clinical trial identification