Priority Research Papers:

Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer

Erik S. Knudsen and Agnieszka K. Witkiewicz _

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Oncotarget. 2016; 7:69111-69123. https://doi.org/10.18632/oncotarget.11588

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Erik S. Knudsen1,2 and Agnieszka K. Witkiewicz1,2,3,4

1 Department of Medicine, University of Arizona, Tucson, AZ, USA

2 University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

3 McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA

4 Department of Pathology, University of Arizona, Tucson, AZ, USA

Correspondence to:

Erik S. Knudsen, email:

Agnieszka K. Witkiewicz, email:

Keywords: CDK4/6, breast cancer, RB-pathway, PAM50, molecular subtypes

Received: May 15, 2016 Accepted: August 13, 2016 Published: August 18, 2016


ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the efficacy of CDK4/6 inhibitors and develop a gene expression signature of CDK4/6 inhibition. CDK4/6 inhibition robustly suppressed cell cycle progression of ER+/HER2- models and complements the activity of limiting estrogen. Chronic treatment with CDK4/6 inhibitors results in the consistent suppression of genes involved in cell cycle, while eliciting the induction of a comparable number of genes involved in multiple processes. The CDK4/6 inhibitor treatment shifted ER+/HER2- models from a high risk (luminal B) to a low risk (luminal A) molecular-phenotype using established gene expression panels. Consonantly, genes repressed by CDK4/6 inhibition are strongly associated with clinical prognosis in ER+/HER2- cases. This gene repression program was conserved in an aggressive triple negative breast cancer xenograft, indicating that this is a common feature of CDK4/6 inhibition. Interestingly, the genes upregulated as a consequence of CDK4/6 inhibition were more variable, but associated with improved outcome in ER+/HER2- clinical cases, indicating dual and heretofore unknown consequence of CDK4/6 inhibition. Interestingly, CDK4/6 inhibition was also associated with the induction of a collection of genes associated with cell growth; but unlike suppression of cell cycle genes this signaling was antagonized by endocrine therapy. Consistent with the stimulation of a mitogenic pathway, cell size and metabolism were induced with CDK4/6 inhibition but ameliorated with endocrine therapy. Together, the data herein support the basis for profound interaction between CDK4/6 inhibitors and endocrine therapy by cooperating for the suppression of cell cycle progression and limiting compensatory pro-growth processes that could contribute to therapeutic failure.

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