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 8

Inhibition of ERBB2 ablates NRG1β/ERBB3-mediated growth in vitro and reduces tumor burden in vivo.

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Inhibition of ERBB2 ablates NRG1β/ERBB3-mediated growth in vitro and red...
(A) A375 cells were plated in the presence of PLX4032 (1 μM) alone or with lapatinib (1 μM), NRG1β (10 ng/ml), or NRG1β combined with lapatinib. Medium and additives were replaced every 3 days, with cells fixed and stained with crystal violet after 7 days. (B) Magnification of colonies in A (×40). (C) Mean fold change ± SEM of tumor volume in 1205Lu xenografts (n = 16 per condition) in nude mice fed either PLX4720 or vehicle chow with or without daily lapatinib (100 mg/kg) by oral gavage. Statistically significant comparisons of the vehicle and lapatinib monotherapy groups are indicated by blue P values, whereas statistically significant comparisons of the PLX4720 monotherapy and PLX4720/lapatinib (PLX + Lap) combined therapy groups are indicated by red P values. (D) Mean fold change ± SEM of tumor volume in A375 xenografts (n = 16 per condition) in nude mice fed either PLX4720 or vehicle-laced chow with or without daily lapatinib (100 mg/kg) by oral gavage. Statistically significant comparisons of the PLX4720 monotherapy and PLX4720/lapatinib combined therapy groups are indicated by their respective P values. (E) Kaplan-Meier plot showing time to 3-fold increase in initial tumor volume of 1205Lu xenografts following treatment with PLX4720 chow alone or with lapatinib (100 mg/kg). P value is indicated. (F) Kaplan-Meier plot showing time to 10-fold increase in initial tumor volume of A375 xenografts following treatment with PLX4720 chow alone or with lapatinib (100 mg/kg). P value is indicated.