Targeting p27 tyrosine phosphorylation as a modality to inhibit CDK4 and CDK2 and cause cell cycle arrest in breast cancer cells

The Cdk4/6 targeting drugs (CDK4i), Palbociclib, Abemaciclib, and Ribociclib, are approved in combination with Estrogen-targeting therapies, such as Letrozole or Fulvestrant, as frontline treatments for metastatic, hormone responsive (ER/PR+), Her2-patients and represent a unique class specifically approved for metastatic disease [1]. Cyclin D-cdk4/6, along with cyclin E-cdk2, controls the G1-S phase transition, and targeting these kinases has long been a type of holy grail in the oncology field. Cyclin D is downstream of most oncogenic signaling pathways, including the Estrogen and Her2 receptors, making cyclin D-cdk4/6 an attractive therapeutic target. However, while combined ER and cdk4/6 targeting significantly extends Progression Free Survival, patients develop resistance and Overall Survival is unchanged, suggesting that there is a need for identifying and specifically targeting these resistance mechanisms