Journal article
Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3
The Journal of clinical investigation, v 123(5), pp 2155-2168
01 May 2013
PMID: 23543055
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The mechanisms underlying adaptive resistance of melanoma to targeted therapies remain unclear. By combining ChIP sequencing with microarray-based gene profiling, we determined that ERBB3 is upregulated by FOXD3, a transcription factor that promotes resistance to RAF inhibitors in melanoma. Enhanced ERBB3 signaling promoted resistance to RAF pathway inhibitors in cultured melanoma cell lines and in mouse xenograft models. ERBB3 signaling was dependent on ERBB2; targeting ERBB2 with lapatinib in combination with the RAF inhibitor PLX4720 reduced tumor burden and extended latency of tumor regrowth in vivo versus PLX4720 alone. These results suggest that enhanced ERBB3 signaling may serve as a mechanism of adaptive resistance to RAF and MEK inhibitors in melanoma and that cotargeting this pathway may enhance the clinical efficacy and extend the therapeutic duration of RAF inhibitors.
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Details
- Title
- Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3
- Creators
- Ethan V. Abel - Thomas Jefferson UniversityKevin J. Basile - Thomas Jefferson UniversityCurtis H. Kugel - Thomas Jefferson UniversityAgnieszka K. Witkiewicz - Thomas Jefferson UniversityKaitlyn Le - Thomas Jefferson UniversityRavi K. Amaravadi - University of PennsylvaniaGiorgos C. Karakousis - University of PennsylvaniaXiaowei Xu - University of PennsylvaniaWei Xu - University of PennsylvaniaLynn M. Schuchter - University of PennsylvaniaJason B. Lee - Thomas Jefferson UniversityAdam Ertel - Thomas Jefferson UniversityPaolo Fortina - Thomas Jefferson UniversityAndrew E. Aplin - Thomas Jefferson University
- Publication Details
- The Journal of clinical investigation, v 123(5), pp 2155-2168
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 14
- Grant note
- W81XWH-11-1-0448 / Department of Defense; United States Department of Defense RSG-08-03-01-CSM / American Cancer Society Dr. Miriam and Sheldon G. Adelson Medical Research Foundation 1P30CA56036 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01-CA160495; R01-GM067893; R01-CA125103 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Joanna M. Nicolay Melanoma Foundation R01GM067893 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01CA125103 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000319025100035
- Scopus ID
- 2-s2.0-84877124454
- Other Identifier
- 991019176795004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental