Cargando…

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

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 profil...

Descripción completa

Detalles Bibliográficos
Autores principales: Knudsen, Erik S., Witkiewicz, Agnieszka K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342463/
https://www.ncbi.nlm.nih.gov/pubmed/27564114
http://dx.doi.org/10.18632/oncotarget.11588
_version_ 1782513185089126400
author Knudsen, Erik S.
Witkiewicz, Agnieszka K.
author_facet Knudsen, Erik S.
Witkiewicz, Agnieszka K.
author_sort Knudsen, Erik S.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5342463
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-53424632017-03-24 Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer Knudsen, Erik S. Witkiewicz, Agnieszka K. Oncotarget Priority Research Paper 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. Impact Journals LLC 2016-08-18 /pmc/articles/PMC5342463/ /pubmed/27564114 http://dx.doi.org/10.18632/oncotarget.11588 Text en Copyright: © 2016 Knudsen and Witkiewicz http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper
Knudsen, Erik S.
Witkiewicz, Agnieszka K.
Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer
title Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer
title_full Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer
title_fullStr Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer
title_full_unstemmed Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer
title_short Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer
title_sort defining the transcriptional and biological response to cdk4/6 inhibition in relation to er+/her2- breast cancer
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342463/
https://www.ncbi.nlm.nih.gov/pubmed/27564114
http://dx.doi.org/10.18632/oncotarget.11588
work_keys_str_mv AT knudseneriks definingthetranscriptionalandbiologicalresponsetocdk46inhibitioninrelationtoerher2breastcancer
AT witkiewiczagnieszkak definingthetranscriptionalandbiologicalresponsetocdk46inhibitioninrelationtoerher2breastcancer