Ligand-Independent EPHA2 signaling drives the adoption of a targeted Therapy-Mediated metastatic melanoma phenotype

Kim H.T. Paraiso; Meghna Das Thakur; Bin Fang; John M. Koomen; Inna V. Fedorenko; Jobin K. John; Hensin Tsao; Keith T. Flaherty; Vernon K. Sondak; Jane L. Messina; Elena B. Pasquale; Alejandro Villagra; Uma N. Rao; John M. Kirkwood; Friedegund Meier; Sarah Sloot; Geoffrey T. Gibney; Darrin Stuart; Hussein Tawbi; Keiran S.M. Smalley

doi:10.1158/2159-8290.CD-14-0293

Ligand-Independent EPHA2 signaling drives the adoption of a targeted Therapy-Mediated metastatic melanoma phenotype

Kim H.T. Paraiso, Meghna Das Thakur, Bin Fang, John M. Koomen, Inna V. Fedorenko, Jobin K. John, Hensin Tsao, Keith T. Flaherty, Vernon K. Sondak, Jane L. Messina, Elena B. Pasquale, Alejandro Villagra, Uma N. Rao, John M. Kirkwood, Friedegund Meier, Sarah Sloot, Geoffrey T. Gibney, Darrin Stuart, Hussein Tawbi, Keiran S.M. Smalley

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

Abstract

Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.

Original language	English (US)
Pages (from-to)	264-273
Number of pages	10
Journal	Cancer discovery
Volume	5
Issue number	3
DOIs	https://doi.org/10.1158/2159-8290.CD-14-0293
State	Published - 2015
Externally published	Yes

ASJC Scopus subject areas

Oncology

Access to Document

10.1158/2159-8290.CD-14-0293

Cite this

Paraiso, K. H. T., Das Thakur, M., Fang, B., Koomen, J. M., Fedorenko, I. V., John, J. K., Tsao, H., Flaherty, K. T., Sondak, V. K., Messina, J. L., Pasquale, E. B., Villagra, A., Rao, U. N., Kirkwood, J. M., Meier, F., Sloot, S., Gibney, G. T., Stuart, D., Tawbi, H., & Smalley, K. S. M. (2015). Ligand-Independent EPHA2 signaling drives the adoption of a targeted Therapy-Mediated metastatic melanoma phenotype. Cancer discovery, 5(3), 264-273. https://doi.org/10.1158/2159-8290.CD-14-0293

Paraiso, KHT, Das Thakur, M, Fang, B, Koomen, JM, Fedorenko, IV, John, JK, Tsao, H, Flaherty, KT, Sondak, VK, Messina, JL, Pasquale, EB, Villagra, A, Rao, UN, Kirkwood, JM, Meier, F, Sloot, S, Gibney, GT, Stuart, D, Tawbi, H & Smalley, KSM 2015, 'Ligand-Independent EPHA2 signaling drives the adoption of a targeted Therapy-Mediated metastatic melanoma phenotype', Cancer discovery, vol. 5, no. 3, pp. 264-273. https://doi.org/10.1158/2159-8290.CD-14-0293

@article{9b78f32968bf47e08bc3352f0d76101d,

title = "Ligand-Independent EPHA2 signaling drives the adoption of a targeted Therapy-Mediated metastatic melanoma phenotype",

abstract = "Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.",

author = "Paraiso, {Kim H.T.} and {Das Thakur}, Meghna and Bin Fang and Koomen, {John M.} and Fedorenko, {Inna V.} and John, {Jobin K.} and Hensin Tsao and Flaherty, {Keith T.} and Sondak, {Vernon K.} and Messina, {Jane L.} and Pasquale, {Elena B.} and Alejandro Villagra and Rao, {Uma N.} and Kirkwood, {John M.} and Friedegund Meier and Sarah Sloot and Gibney, {Geoffrey T.} and Darrin Stuart and Hussein Tawbi and Smalley, {Keiran S.M.}",

note = "Publisher Copyright: {\textcopyright}2014 American Association for Cancer Research.",

year = "2015",

doi = "10.1158/2159-8290.CD-14-0293",

language = "English (US)",

volume = "5",

pages = "264--273",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

TY - JOUR

T1 - Ligand-Independent EPHA2 signaling drives the adoption of a targeted Therapy-Mediated metastatic melanoma phenotype

AU - Paraiso, Kim H.T.

AU - Das Thakur, Meghna

AU - Fang, Bin

AU - Koomen, John M.

AU - Fedorenko, Inna V.

AU - John, Jobin K.

AU - Tsao, Hensin

AU - Flaherty, Keith T.

AU - Sondak, Vernon K.

AU - Messina, Jane L.

AU - Pasquale, Elena B.

AU - Villagra, Alejandro

AU - Rao, Uma N.

AU - Kirkwood, John M.

AU - Meier, Friedegund

AU - Sloot, Sarah

AU - Gibney, Geoffrey T.

AU - Stuart, Darrin

AU - Tawbi, Hussein

AU - Smalley, Keiran S.M.

PY - 2015

Y1 - 2015

N2 - Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.

AB - Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.

UR - http://www.scopus.com/inward/record.url?scp=84925297806&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925297806&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-14-0293

DO - 10.1158/2159-8290.CD-14-0293

M3 - Article

C2 - 25542447

AN - SCOPUS:84925297806

SN - 2159-8274

VL - 5

SP - 264

EP - 273

JO - Cancer discovery

JF - Cancer discovery

IS - 3

ER -

Ligand-Independent EPHA2 signaling drives the adoption of a targeted Therapy-Mediated metastatic melanoma phenotype

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this