Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3
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
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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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 7

ERBB2 is required for NRG1β/ERBB3 signaling in melanoma.

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ERBB2 is required for NRG1β/ERBB3 signaling in melanoma. (A) Representat...
(A) Representative images of A375 xenografts taken from animals fed vehicle or PLX4720-laced chow for 5 days analyzed by IHC for phospho-ERBB2 (Y1221/Y1222). Original magnification, ×100. (B) Quantitation of phospho-ERBB2 intensity of tumor cells from vehicle (n = 5) or PLX4720-treated A375 xenografts (n = 5). *P = 0.001. (C) WM115 cells were transfected with control or ERBB2-targeting siRNA for 72 hours, then treated with PLX4720 or DMSO for an additional 24 hours followed by treatment with or without NRG1β (10 ng/ml) for 1 hour, lysed, and immunoblotted as indicated. (D) A375 cells were pretreated for 24 hours with PLX4032 (1 μM) and then treated with or without NRG1β and a dose range of lapatinib for 1 hour, lysed, and immunoblotted as indicated.