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posted on 2023-03-31, 01:46 authored by Eric Metzger, Stella S. Stepputtis, Juliane Strietz, Bogdan-Tiberius Preca, Sylvia Urban, Dominica Willmann, Anita Allen, Fides Zenk, Nicola Iovino, Peter Bronsert, Amelie Proske, Marie Follo, Melanie Boerries, Elmar Stickeler, Jiangchun Xu, Michael B. Wallace, Jeffrey A. Stafford, Toufike Kanouni, Jochen Maurer, Roland Schüle KDM4B, C, or D do not control proliferation and xenograft tumor growth of BCSC1.
Funding
European Research Council
Deutsche Forschungsgemeinschaft
German Federal Ministry of Education and Research
History
ARTICLE ABSTRACT
Traditional treatments for breast cancer fail to address therapy-resistant cancer stem–like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem–like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900–12. ©2017 AACR.
