Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target

Author(s):Show less -

Chen, Guo ^[1] ; Chakravarti, Nitin ^[2] ; Aardalen, Kimberly ^[3] ; Lazar, Alexander J. ^[2] ; Tetzlaff, Michael T. ^[2] ; Wubbenhorst, Bradley ^[4] ; Kim, Sang-Bae ^[5] ; Kopetz, Scott ^[6] ; Ledoux, Alicia A. ^[2] ; Gopal, Y. N. Vashisht ^[1] ; Pereira, Cristiano Goncalves ^[1] ; Deng, Wanleng ^[1] ; Lee, Ju-Seog ^[5] ; Nathanson, Katherine L. ^[4] ; Aldape, Kenneth D. ^[2] ; Prieto, Victor G. ^[2] ; Stuart, Darrin ^[3] ; Davies, Michael A. ^{[1, 5]}

Affiliation

^[1] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 - USA

^[2] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 - USA

^[3] Novartis Inst Biomed Res, Emeryville, CA - USA

^[4] Univ Penn, Sch Med, Dept Med, Div Med Genet, Philadelphia, PA 19104 - USA

^[5] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 - USA

^[6] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 - USA

• Document type: Journal article
• Source: Clinical Cancer Research; v. 20, n. 21, p. 5537-5546, NOV 1 2014.
• Web of Science Citations: 62

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. (C) 2014 AACR. (AU)

• FAPESP's process: 12/24056-2 - Functional characterization of melanoma-restricted genes (RMELs) associated with melanoma progression and BRAF V600E mutation
• Grantee: Cristiano Gonçalves Pereira
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate