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

Publication ,  Journal Article
Wardell, SE; Ellis, MJ; Alley, HM; Eisele, K; VanArsdale, T; Dann, SG; Arndt, KT; Primeau, T; Griffin, E; Shao, J; Crowder, R; Lai, J-P ...
Published in: Clin Cancer Res
November 15, 2015

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 15, 2015

Volume

21

Issue

22

Start / End Page

5121 / 5130

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tamoxifen
  • Selective Estrogen Receptor Modulators
  • Pyridines
  • Piperazines
  • Oncology & Carcinogenesis
  • Mutation
  • Mice
  • MCF-7 Cells
  • Humans
 

Citation

APA
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Wardell, S. E., Ellis, M. J., Alley, H. M., Eisele, K., VanArsdale, T., Dann, S. G., … Li, S. (2015). Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res, 21(22), 5121–5130. https://doi.org/10.1158/1078-0432.CCR-15-0360
Wardell, Suzanne E., Matthew J. Ellis, Holly M. Alley, Koleen Eisele, Todd VanArsdale, Stephen G. Dann, Kim T. Arndt, et al. “Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.Clin Cancer Res 21, no. 22 (November 15, 2015): 5121–30. https://doi.org/10.1158/1078-0432.CCR-15-0360.
Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, et al. Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res. 2015 Nov 15;21(22):5121–30.
Wardell, Suzanne E., et al. “Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.Clin Cancer Res, vol. 21, no. 22, Nov. 2015, pp. 5121–30. Pubmed, doi:10.1158/1078-0432.CCR-15-0360.
Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, Arndt KT, Primeau T, Griffin E, Shao J, Crowder R, Lai J-P, Norris JD, McDonnell DP, Li S. Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res. 2015 Nov 15;21(22):5121–5130.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 15, 2015

Volume

21

Issue

22

Start / End Page

5121 / 5130

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tamoxifen
  • Selective Estrogen Receptor Modulators
  • Pyridines
  • Piperazines
  • Oncology & Carcinogenesis
  • Mutation
  • Mice
  • MCF-7 Cells
  • Humans