KDM4 inhibition targets breast cancer stem-like cells
Metzger E, Stepputtis SS, Strietz J, Preca BT, Urban S, Willmann D, Allen A, Zenk F, Iovino N, Bronsert P, Proske A, Follo M, Boerries M, Stickeler E, Xu J, Wallace MB, Stafford JA, Kanouni T, Maurer J, Schüle R.
Traditional treatments for breast cancer fail to address therapy-resistant cancer stemlike 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 BCSC 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.