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

Authors
  • Liu, Xiaoni1, 2
  • Zhang, Shang-Min1
  • McGeary, Meaghan K1, 2
  • Krykbaeva, Irina1, 2
  • Lai, Ling3
  • Jansen, Daniel J4
  • Kales, Stephen C4
  • Simeonov, Anton4
  • Hall, Matthew D4
  • Kelly, Daniel P3
  • Bosenberg, Marcus W5, 2, 6
  • Yan, Qin5
  • 1 Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
  • 2 Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.
  • 3 Penn Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 4 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland.
  • 5 Department of Pathology, Yale School of Medicine, New Haven, Connecticut. [email protected] [email protected]
  • 6 Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut.
Type
Published Article
Journal
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research
Publication Date
Mar 01, 2019
Volume
18
Issue
3
Pages
706–717
Identifiers
DOI: 10.1158/1535-7163.MCT-18-0395
PMID: 30523048
Source
Medline
Language
English
License
Unknown

Abstract

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. ©2018 American Association for Cancer Research.

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