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Clin Cancer Res. 2017 Sep 15;23(18):5561-5572. doi: 10.1158/1078-0432.CCR-17-0369. Epub 2017 Jun 12.

Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer.

Author information

1
Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, United Kingdom.
2
The Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
3
Department of Translational Oncology, Genentech (Roche Group), Genentech, South San Francisco, California.
4
Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, United Kingdom. nicholas.turner@icr.ac.uk.
5
Breast Unit, The Royal Marsden Hospital, London, United Kingdom.

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.

PMID:
28606920
PMCID:
PMC6175044
DOI:
10.1158/1078-0432.CCR-17-0369
[Indexed for MEDLINE]
Free PMC Article

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