4.6 Article

KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations

Journal

MOLECULAR CANCER THERAPEUTICS
Volume 18, Issue 3, Pages 706-717

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-18-0395

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Funding

  1. NIH Yale SPORE in Skin Cancer [NCI P50 CA121974]
  2. Department of Defense Peer-Reviewed Cancer Research Program [W81XWH-13-10235, W81XWH-16-1-0306]
  3. Melanoma Research Foundation [R01 CA196660, P01 CA128814]
  4. Melanoma Research Alliance
  5. American Skin Association
  6. Hervey Family Foundation
  7. Yale Cancer Center [NCI P30 CA16359, T32CA193200, F30 CA228444]
  8. federal funds from the NCI, NIH, under Chemical Biology Consortium [HHSN261200800001E]
  9. NCATS, NIH

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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 BRAF(V600E) 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.

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