Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer
AffiliationUniv Arizona, Dept Med
Univ Arizona, Ctr Canc
Univ Arizona, Dept Pathol
MetadataShow full item record
PublisherIMPACT JOURNALS LLC
CitationKnudsen, Erik S., and Agnieszka K. Witkiewicz. "Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2-breast cancer." Oncotarget 7.43 (2016): 69111-69123.
RightsAll site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractER 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.
VersionFinal published version
SponsorsNIH [CA129134, CA188650, CA163863]