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Clin Cancer Res. 2015 Nov 15;21(22):5121-5130. doi: 10.1158/1078-0432.CCR-15-0360. Epub 2015 May 19.

Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.

Author information

1
Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, NC 27710.
2
Lester and Sue Smith Breast Center, Baylor College of Medicine Houston TX 77030.
3
Pfizer Oncology Research Unit La Jolla, CA 92121.
4
Pfizer Oncology Research Unit Pearl River, NY 10965.
5
Division of Oncology, Department of Internal Medicine Washington University in St Louis, MO 63110.
6
Department of Pathology Saint Louis University, MO 63104.
7
Siteman Cancer Center Breast Cancer Program Washington University in St. Louis, MO 63110.
#
Contributed equally

Abstract

PURPOSE:

Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy-resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD- or SSH-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant ESR1(+) breast cancer.

EXPERIMENTAL DESIGN:

SERDs, SSHs, and the CDK4/6 inhibitor palbociclib were evaluated as single agents or in combination in established cellular and animal models of endocrine therapy-resistant ESR1(+) breast cancer.

RESULTS:

The combination of palbociclib with a SERD or an SSH was shown to effectively inhibit the growth of MCF7 cell or ESR1-mutant patient-derived tumor xenografts. In tamoxifen-resistant MCF7 xenografts, the palbociclib/SERD or SSH combination resulted in an increased duration of response as compared with either drug alone.

CONCLUSIONS:

A SERD- or SSH-palbociclib combination has therapeutic potential in breast tumors resistant to endocrine therapies or those expressing ESR1 mutations. See related commentary by DeMichele and Chodosh, p. 4999.

PMID:
25991817
PMCID:
PMC4644714
DOI:
10.1158/1078-0432.CCR-15-0360
[Indexed for MEDLINE]
Free PMC Article

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