Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer.
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Embargo End Date
Authors
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
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
Document Type
Journal Article
Date
2017-09-15
Date Accepted
2017-06-05
Abstract
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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (18), pp. 5561 - 5572
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Research Team
Molecular Oncology
Dynamical Cell Systems
Dynamical Cell Systems