Chen, G, Chakravarti, N, Aardalen, K, Lazar, AJ, Tetzlaff, MT, Wubbenhorst, B, Kim, SB, Kopetz, S, Ledoux, AA, Gopal, YN, Pereira, CG, Deng, W, Lee, JS, Nathanson, KL, Aldape, KD, Prieto, VG, Stuart, D and Davies, MA (2014) Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target. Clin Cancer Res . pp. 5537-5546.

Abstract

PURPOSE: An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. EXPERIMENTAL DESIGN: Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. RESULTS: The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases. CONCLUSIONS: These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors. Clin Cancer Res; 20(21); 5537-46. (c)2014 AACR

Item Type:	Article
Additional Information:	NIBR author: Aardalen, K institute: NIBR contributor address: Departments of Melanoma Medical Oncology, gchen2@mdanderson.orgPathologyNovartis Institutes for Biomedical Research, Emeryville, California; andPathologyPathologyDivision of Medical Genetics, Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSystems Biology andGastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas;PathologyDepartments of Melanoma Medical OncologyDepartments of Melanoma Medical OncologyDepartments of Melanoma Medical OncologySystems Biology andDivision of Medical Genetics, Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaPathologyPathologyNovartis Institutes for Biomedical Research, Emeryville, California; andDepartments of Melanoma Medical Oncology, Systems Biology and
Date Deposited:	13 Oct 2015 13:11
Last Modified:	13 Oct 2015 13:11
URI:	https://oak.novartis.com/id/eprint/24256