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

Erik S. Knudsen, Agnieszka K. Witkiewicz

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)69111-69123
Number of pages13
JournalOncotarget
Volume7
Issue number43
DOIs
StatePublished - 2016

Fingerprint

Breast Neoplasms
Genes
Cell Cycle
Therapeutics
Estrogens
Triple Negative Breast Neoplasms
cdc Genes
Gene Expression Profiling
Growth
Cell Size
Transcriptome
Heterografts
Disease-Free Survival
Phenotype
Gene Expression

Keywords

  • Breast cancer
  • CDK4/6
  • Molecular subtypes
  • PAM50
  • RB-pathway

ASJC Scopus subject areas

  • Oncology

Cite this

Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2-breast cancer. / Knudsen, Erik S.; Witkiewicz, Agnieszka K.

In: Oncotarget, Vol. 7, No. 43, 2016, p. 69111-69123.

Research output: Contribution to journalArticle

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