KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2019
- Source ID
- 10.1158/1535-7163.mct-18-0395
Entities
People
- Anton Simeonov
- Daniel J. Jansen
- Daniel P. Kelly
- Irina Krykbaeva
- Ling Lai
- Marcus W. Bosenberg
- Matthew D. Hall
- Meaghan K McGeary
- Qin Yan
- Shang-min Zhang
- Stephen C. Kales
- Xiaoni Liu
Organizations
- American Skin Association
- Congressionally Directed Medical Research Programs
- Melanoma Research Alliance
- Melanoma Research Foundation
- National Cancer Institute
- National Center for Advancing Translational Sciences
- National Institutes of Health
- University of Pennsylvania
- Yale School of Medicine