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Cancer Res. 2016 Apr 15;76(8):2301-13. doi: 10.1158/0008-5472.CAN-15-0728. Epub 2016 Mar 28.

Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer.

Author information

1
The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
2
Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
3
Weill Cornell Medicine, Cornell University, New York, New York.
4
Medical Oncology, Hospital Vall d'Hebron, Spain.
5
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
6
The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom. Academic Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom.
7
The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom. Breast Unit, Royal Marsden Hospital, London, United Kingdom. nicholas.turner@icr.ac.uk vserra@vhio.net.
8
Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. nicholas.turner@icr.ac.uk vserra@vhio.net.

Abstract

Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1-S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301-13.

PMID:
27020857
PMCID:
PMC5426059
DOI:
10.1158/0008-5472.CAN-15-0728
[Indexed for MEDLINE]
Free PMC Article

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