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

Ethan V. Abel, Kevin J. Basile, Curtis H. Kugel, 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

Research output: Contribution to journalArticle

133 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2155-2168
Number of pages14
JournalJournal of Clinical Investigation
Volume123
Issue number5
DOIs
StatePublished - May 1 2013

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Melanoma
Up-Regulation
Tumor Burden
Heterografts
Cultured Cells
Transcription Factors
Cell Line
Therapeutics
Genes
Neoplasms
PLX 4720

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Abel, E. V., Basile, K. J., Kugel, C. H., Witkiewicz, A. K., Le, K., Amaravadi, R. K., ... Aplin, A. E. (2013). Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. Journal of Clinical Investigation, 123(5), 2155-2168. https://doi.org/10.1172/JCI65780

Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. / Abel, Ethan V.; Basile, Kevin J.; Kugel, Curtis H.; Witkiewicz, Agnieszka K.; Le, Kaitlyn; Amaravadi, Ravi K.; Karakousis, Giorgos C.; Xu, Xiaowei; Xu, Wei; Schuchter, Lynn M.; Lee, Jason B.; Ertel, Adam; Fortina, Paolo; Aplin, Andrew E.

In: Journal of Clinical Investigation, Vol. 123, No. 5, 01.05.2013, p. 2155-2168.

Research output: Contribution to journalArticle

Abel, EV, Basile, KJ, Kugel, CH, Witkiewicz, AK, Le, K, Amaravadi, RK, Karakousis, GC, Xu, X, Xu, W, Schuchter, LM, Lee, JB, Ertel, A, Fortina, P & Aplin, AE 2013, 'Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3', Journal of Clinical Investigation, vol. 123, no. 5, pp. 2155-2168. https://doi.org/10.1172/JCI65780
Abel, Ethan V. ; Basile, Kevin J. ; Kugel, Curtis H. ; Witkiewicz, Agnieszka K. ; Le, Kaitlyn ; Amaravadi, Ravi K. ; Karakousis, Giorgos C. ; Xu, Xiaowei ; Xu, Wei ; Schuchter, Lynn M. ; Lee, Jason B. ; Ertel, Adam ; Fortina, Paolo ; Aplin, Andrew E. / Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 5. pp. 2155-2168.
@article{82776339933842c1beeffe55dec737ab,
title = "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.",
author = "Abel, {Ethan V.} and Basile, {Kevin J.} and Kugel, {Curtis H.} and Witkiewicz, {Agnieszka K.} and Kaitlyn Le and Amaravadi, {Ravi K.} and Karakousis, {Giorgos C.} and Xiaowei Xu and Wei Xu and Schuchter, {Lynn M.} and Lee, {Jason B.} and Adam Ertel and Paolo Fortina and Aplin, {Andrew E.}",
year = "2013",
month = "5",
day = "1",
doi = "10.1172/JCI65780",
language = "English (US)",
volume = "123",
pages = "2155--2168",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3

AU - Abel, Ethan V.

AU - Basile, Kevin J.

AU - Kugel, Curtis H.

AU - Witkiewicz, Agnieszka K.

AU - Le, Kaitlyn

AU - Amaravadi, Ravi K.

AU - Karakousis, Giorgos C.

AU - Xu, Xiaowei

AU - Xu, Wei

AU - Schuchter, Lynn M.

AU - Lee, Jason B.

AU - Ertel, Adam

AU - Fortina, Paolo

AU - Aplin, Andrew E.

PY - 2013/5/1

Y1 - 2013/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84877124454&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877124454&partnerID=8YFLogxK

U2 - 10.1172/JCI65780

DO - 10.1172/JCI65780

M3 - Article

VL - 123

SP - 2155

EP - 2168

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -