Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy-Mediated Metastatic Melanoma Phenotype

被引:88
作者
Paraiso, Kim H. T. [1 ]
Das Thakur, Meghna [2 ]
Fang, Bin [3 ]
Koomen, John M. [1 ]
Fedorenko, Inna V. [4 ]
John, Jobin K. [1 ]
Tsao, Hensin [5 ]
Flaherty, Keith T. [6 ]
Sondak, Vernon K. [7 ]
Messina, Jane L. [7 ,8 ]
Pasquale, Elena B. [9 ]
Villagra, Alejandro [10 ]
Rao, Uma N. [11 ]
Kirkwood, John M. [11 ]
Meier, Friedegund [12 ]
Sloot, Sarah [7 ]
Gibney, Geoffrey T. [7 ]
Stuart, Darrin [2 ]
Tawbi, Hussein [11 ]
Smalley, Keiran S. M. [4 ,7 ]
机构
[1] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL 33612 USA
[2] Novartis Inst Biomed Res, Emeryville, CA USA
[3] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Prote Core, Tampa, FL 33612 USA
[4] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Tumor Biol, Tampa, FL 33612 USA
[5] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA
[6] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA
[7] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Cutaneous Oncol, Tampa, FL 33612 USA
[8] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Anat Pathol, Tampa, FL 33612 USA
[9] Sanford Burnham Med Res Inst, La Jolla, CA USA
[10] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL 33612 USA
[11] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol,Canc Inst, Pittsburgh, PA 15213 USA
[12] Univ Tubingen, Dept Dermatooncol, Tubingen, Germany
关键词
ACQUIRED-RESISTANCE; MUTANT MELANOMA; MEK INHIBITION; UP-REGULATION; BRAF; PLASTICITY; RECEPTORS; INVASION; VEMURAFENIB; CELLS;
D O I
10.1158/2159-8290.CD-14-0293
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. SIGNIFICANCE: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites. (C) 2014 AACR.
引用
收藏
页码:264 / 273
页数:10
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