In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1864-1864
Kurzfassung:
The majority of breast cancers express and rely on ERα for tumor growth, thus endocrine therapy is the mainstay of ER-positive breast cancer treatment. Despite the effectiveness of current therapies, many patients relapse with tumors still dependent on ER for growth via both estrogen-dependent and estrogen-independent mechanisms. Acquired mutations in ESR1 were recently identified in the ligand-binding domain of ERα in patients who progressed after aromatase inhibitors and tamoxifen. It is estimated that more than 20% of relapsed ER-positive breast cancer patients acquire activating mutations in ESR1. We created a variety of model systems to study the functional consequences of ESR1 mutations. In stable overexpressing cell lines, the mutant ER protein eventually becomes down-regulated, thus we generated cell lines with dox-inducible and CRISPR engineered ESR1 hotspot mutations. We confirmed ligand-independent transcriptional activity of ESR1 hotspot mutations including Y537S and D538G. Cell lines and patient derived xenograft (PDX) models were utilized in ER ChIP-seq studies. Additionally, we investigated therapeutic response and resistance in the context of ESR1 activating mutations for tamoxifen, fulvestrant, and next generation oral SERDs including ARN-810, also known as GDC-0810. ARN-810 is efficacious in MCF7 ESR1 Y537S xenografts and WHIM20 Y537S PDX tumors, indicating that SERDs may be effective for ER mutants. Citation Format: Wei Zhou, Robert A. Blake, Jim Nonomiya, Jing Qian, Lorna Kategaya, Ingrid Wertz, Anneleen Daemen, Thomas O'Brien, John Sensintaffar, Michael Moon, Michelle A. Nannini, Jason Oeh, Deepak Sampath, Xiaojing Wang, Nicholas Smith, Daniel Brigham, James Joseph, Jeffrey H. Hager, Lori S. Friedman. Selective estrogen receptor degrader (SERD) activity in ESR1 mutant models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1864. doi:10.1158/1538-7445.AM2015-1864
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-1864
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2015
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
