Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer.
Date
2017-09-15ICR Author
Author
Asghar, US
Barr, AR
Cutts, R
Beaney, M
Babina, I
Sampath, D
Giltnane, J
Lacap, JA
Crocker, L
Young, A
Pearson, A
Herrera-Abreu, MT
Bakal, C
Turner, NC
Type
Journal Article
Metadata
Show full item recordAbstract
Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes and investigated mechanisms of sensitivity.Experimental Design: A panel of cell lines representative of TNBC was tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single-cell analysis in conjunction with time-lapse imaging.Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro (P < 0.001 LAR vs. basal-like) and in vivo in MDA-MB-453 LAR cell line xenografts. Single-cell analysis of CDK2 activity demonstrated differences in cell-cycle dynamics between LAR and basal-like cells. Palbociclib-sensitive LAR cells exit mitosis with low levels of CDK2 activity, into a quiescent state that requires CDK4/6 activity for cell-cycle reentry. Palbociclib-resistant basal-like cells exit mitosis directly into a proliferative state, with high levels of CDK2 activity, bypassing the restriction point and the requirement for CDK4/6 activity. High CDK2 activity after mitosis is driven by temporal deregulation of cyclin E1 expression. CDK4/6 inhibitors were synergistic with PI3 kinase inhibitors in PIK3CA-mutant TNBC cell lines, extending CDK4/6 inhibitor sensitivity to additional TNBC subtypes.Conclusions: Cell-cycle dynamics determine the response to CDK4/6 inhibition in TNBC. CDK4/6 inhibitors, alone and in combination, are a novel therapeutic strategy for specific subgroups of TNBC. Clin Cancer Res; 23(18); 5561-72. ©2017 AACR.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Disease Models, Animal
Piperazines
Pyridines
Receptors, Androgen
Antineoplastic Agents
Protein Kinase Inhibitors
Signal Transduction
Mitosis
Cell Proliferation
Cell Survival
Drug Resistance, Neoplasm
Phenotype
Female
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Molecular Imaging
Phosphatidylinositol 3-Kinases
Time-Lapse Imaging
Single-Cell Analysis
Triple Negative Breast Neoplasms
Research team
Molecular Oncology
Dynamical Cell Systems
Language
eng
Date accepted
2017-06-05
License start date
2017-09
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (18), pp. 5561 - 5572
Publisher
AMER ASSOC CANCER RESEARCH