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Series GSE150997 Query DataSets for GSE150997
Status Public on Dec 04, 2021
Title Activation of the interferon signaling pathway is associated with resistance to CDK4/6 inhibitors and immune checkpoint activation in ER-positive breast cancer [RNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary CDK4/6 inhibitors are highly effective against ER+/HER2- breast cancer (BC); however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6 inhibitors may lead to the identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Parental BC cells and their endocrine-resistant derivatives (EndoR) were used in this study. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. We found that parental and EndoR BC lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high Interferon (IFN) signaling and reduced sensitivity to CDK4/6 inhibitors, thus an ‘IFN-Related Palbociclib-Resistance Signature’ (IRPS) was derived. In two neoadjuvant trials of a CDK4/6 inhibitor plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6 inhibition. PalboR derivatives displayed a dramatic activation of IFN/STAT1-signaling compared to their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Our study demonstrates that aberrant IFN-signaling is associated with intrinsic resistance to CDK4/6 inhibitors. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN-pathway, which warrants additional studies to clarify its involvement in resistance to CDK4/6 inhibitors.
 
Overall design RNA-seq of ER+ breast cancer cell models and derivatives with resistance to endocrine therapy or dual resistance to estrogen deprivation and palbociclib, in duplicates, using Illumina NextSeq500.
 
Contributor(s) Jeselsohn R, Brown M, Schiff R, Fu X, De Angelis C, Nardone A
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Submission date May 21, 2020
Last update date Dec 06, 2021
Contact name Rinath Jeselsohn
Organization name DFCI
Department Medical Oncology
Lab Jeselsohn Lab
Street address 450 Brookline Ave, D728
City Boston
State/province MD
ZIP/Postal code 02215
Country USA
 
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (33)
GSM4563845 MCF7-EDR/PalboR rep1
GSM4563846 MCF7-EDR/PalboR rep2
GSM4563847 MCF7-EDR rep1
Relations
BioProject PRJNA634350
SRA SRP262641

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE150997_Cuff_Gene_Counts_T47D_Italy.csv.gz 346.3 Kb (ftp)(http) CSV
GSE150997_RAW.tar 6.9 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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