Molecular determinants of resistance to CDK4/6 inhibition in ER+ breast cancer

An abstract of a study by Luo et al examining the molecular determinants of resistance to CDK4/6 inhibition in ER+ breast cancer is presented. To this end, we have generated cultured to resistance (CTR) models and conducted genome-wide open reading frame (ORF) screens. Whereas CDK4/6 inhibition down...

Full description

Saved in:
Bibliographic Details
Published in:European journal of cancer (1990) 2016-12, Vol.69, p.S76-S76
Main Authors: Luo, F, Cowley, G, Garraway, L
Format: Article
Language:English
Subjects:
Breast cancer
Cancer
Cell cycle
Cells
Charcoal
CRISPR
Cyclin-dependent kinase 4
Deprivation
Estrogen receptors
Estrogens
Genomes
Hematology, Oncology and Palliative Medicine
Impact resistance
Inhibition
Molecular chains
Screens
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:An abstract of a study by Luo et al examining the molecular determinants of resistance to CDK4/6 inhibition in ER+ breast cancer is presented. To this end, we have generated cultured to resistance (CTR) models and conducted genome-wide open reading frame (ORF) screens. Whereas CDK4/6 inhibition downregulates phosphorylated RB and CCNE2 in sensitive ER+ breast cancer cells, these markers are maintained in CTR cells. CRISPR RB1 knockout breast cancer cells are also more resistant to palbociclib than abemaciclib. Since RB is the main gatekeeper of G1/S cell cycle progression, our results suggest that abemaciclib may have relevant off-target activity in ER+ breast cancer. Furthermore, it is unclear how estrogen may impact resistance to CDK4/6 inhibition or whether acquired resistance may differ between inhibitors. Thus, we have conducted near genome-wide open reading frame (ORF) screens to uncover the molecular determinants of resistance to palbociclib and abemaciclib. ER+ breast cancer cells were infected with Broad Institute's 17,255 ORF collection in a pooled format, selected and subsequently cultivated in the presence of (1) full serum (FBS) + palbociclib, (2) FBS + abemaciclib, (3) charcoal-stripped serum (CSS) to mimic estrogen-deprivation, (4) CSS + palbociclib or (5) CSS + abemaciclib.
ISSN:0959-8049
1879-0852
DOI:10.1016/S0959-8049(16)32819-2