@article{33c1e5cd116b4faca637502f06864fa3,
title = "KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance",
abstract = "Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.",
keywords = "acquired resistance, barcoding, cellular heterogeneity, endocrine resistance, epigenetic, KDM5B, pre-existing resistance, single-cell RNA-seq, subclonal fraction, transcriptomic heterogeneity",
author = "Kunihiko Hinohara and Wu, {Hua Jun} and S{\'e}bastien Vigneau and McDonald, {Thomas O.} and Igarashi, {Kyomi J.} and Yamamoto, {Kimiyo N.} and Thomas Madsen and Anne Fassl and Egri, {Shawn B.} and Malvina Papanastasiou and Lina Ding and Guillermo Peluffo and Ofir Cohen and Kales, {Stephen C.} and Madhu Lal-Nag and Ganesha Rai and Maloney, {David J.} and Ajit Jadhav and Anton Simeonov and Nikhil Wagle and Myles Brown and Alexander Meissner and Piotr Sicinski and Jaffe, {Jacob D.} and Rinath Jeselsohn and Gimelbrant, {Alexander A.} and Franziska Michor and Kornelia Polyak",
note = "Funding Information: P.S., M.B., N.W., and K.P. received research support and were consultants to Novartis Institutes for BioMedical Research during the execution of this study. K.P. and M.B. serves on the scientific advisory board of Mitra Biotech and Kronos Bio, respectively. R.J. receives research support from Pfizer. N.W. was a shareholder of Foundation Medicine and a consultant to Eli Lilly during the execution of this study, and he currently receives research support from Puma Biotechnologies. L.D. is current employee of Cugene. Funding Information: We thank members of our laboratories for their critical reading of this manuscript and useful discussions. We thank members of Allon Klein's laboratory and the Single Cell Core at Harvard Medical School, particularly Allon Klein, Rapolas Zilionis, Sarah Boswell, and Alex Ratner, for providing instructions and guidance for setting up our single-cell RNA sequencing system. We thank Bob Yauch (Genentech, San Francisco) for providing us the KDM5 inhibitor 48 and the Lurie Family Imaging Center for performing the in vivo xenograft experiments. This research was supported by the National Cancer Institute PSOC U54 CA193461 (to F.M. and K.P.), R35 CA197623 (to K.P.), P01 CA080111 (to K.P., M.B., and P.S.), R01 CA202634 (to P.S.), the Ludwig Center at Harvard (to K.P., F.M., and M.B.), and the Division of Preclinical Innovation of the National Center for Advancing Translational Sciences (NCATS), NIH (to S.C.K., A.S., D.J.M., G.R., A.J., and M.L.-N.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = dec,
day = "10",
doi = "10.1016/j.ccell.2018.10.014",
language = "English",
volume = "34",
pages = "939--953.e9",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}
