Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3
Ethan V. Abel, … , Paolo Fortina, Andrew E. Aplin
Ethan V. Abel, … , Paolo Fortina, Andrew E. Aplin
Published April 1, 2013
Citation Information: J Clin Invest. 2013;123(5):2155-2168. https://doi.org/10.1172/JCI65780.
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Research Article Oncology

Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3

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.

Authors

Ethan V. Abel, Kevin J. Basile, Curtis H. Kugel III, Agnieszka K. Witkiewicz, Kaitlyn Le, Ravi K. Amaravadi, Giorgos C. Karakousis, Xiaowei Xu, Wei Xu, Lynn M. Schuchter, Jason B. Lee, Adam Ertel, Paolo Fortina, Andrew E. Aplin

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Figure 4

FOXD3 and RAF/MEK inhibition enhance responsiveness to NRG1β.

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FOXD3 and RAF/MEK inhibition enhance responsiveness to NRG1β. (A and B) ...
(A and B) WM115TR/FOXD3-V5 (A) or WM115 (B) were treated with or without Dox (100 ng/ml) or PLX4032 (1 μM), respectively, for 24 hours followed by treatment with the indicated concentration of NRG1β for 1 hour. Cell lysates were immunoblotted as indicated. (C) WM115 cells were treated overnight with DMSO, PLX4032 (1 μM), or AZD6244 (3.3 μM), followed by 1 additional hour with or without NRG1β (10 ng/ml). Cells were lysed and lysates immunoblotted as indicated. (D) WM115 cells were pretreated with PLX4032 for 0, 2, 4, 6, and 16 hours and then stimulated with NRG1β (10 ng/ml) for 30 minutes. Cell lysates were immunoblotted as indicated. (E) WM115 cells were transfected with either control siRNA or 2 distinct FOXD3-targeting siRNAs for 72 hours. Cells were then treated for an additional 24 hours with PLX4032 (1 μM) or DMSO, after which NRG1β (10 ng/ml) was added for an additional hour to activate ERBB3. Cell lysates were immunoblotted as indicated.