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Mol Cancer Ther. 2019 Mar;18(3):706-717. doi: 10.1158/1535-7163.MCT-18-0395. Epub 2018 Dec 6.

KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations.

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Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.
Penn Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland.
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut.
Contributed equally


Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75- (CD34+) and CD34-p75- (CD34-) tumor subpopulations were characterized as melanoma-propagating cells (MPC) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemoresistance. In this study, we demonstrate that CD34+ and CD34- subpopulations carrying the BRAFV600E mutation confer differential sensitivity to targeted BRAF inhibition. Through elevated KDM5B expression, melanoma cells shift toward a more drug-tolerant, CD34- state upon exposure to BRAF inhibitor or combined BRAF inhibitor and MEK inhibitor treatment. KDM5B loss or inhibition shifts melanoma cells to the more BRAF inhibitor-sensitive CD34+ state. These results support that KDM5B is a critical epigenetic regulator that governs the transition of key MPC subpopulations with distinct drug sensitivity. This study also emphasizes the importance of continuing to advance our understanding of intratumor heterogeneity and ultimately develop novel therapeutics by altering the heterogeneous characteristics of melanoma.

[Available on 2020-03-01]

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