Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3.
Publication/Presentation Date
5-1-2013
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.
Volume
123
Issue
5
First Page
2155
Last Page
2168
ISSN
1558-8238
Published In/Presented At
Abel, E. V., Basile, K. J., Kugel, C. H., 3rd, Witkiewicz, A. K., Le, K., Amaravadi, R. K., Karakousis, G. C., Xu, X., Xu, W., Schuchter, L. M., Lee, J. B., Ertel, A., Fortina, P., & Aplin, A. E. (2013). Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. The Journal of clinical investigation, 123(5), 2155–2168. https://doi.org/10.1172/JCI65780
Disciplines
Medicine and Health Sciences
PubMedID
23543055
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article