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Updated: Apr 30, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a
Guo Chen1, Nitin Chakravarti2, Kimberly Aardalen3
1Departments of Melanoma Medical Oncology, gchen2@mdanderson.org.
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.
Insights
Melanoma brain metastases show increased PI3K/AKT pathway activation compared to extracranial sites. This finding supports targeting the PI3K/AKT pathway for treating these aggressive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Melanoma brain metastases are a frequent and severe complication of advanced melanoma.
- Understanding molecular differences between brain and extracranial metastases is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate molecular differences between melanoma brain metastases and extracranial metastases.
- To identify potential therapeutic targets specific to brain metastases.
Main Methods:
- Analysis of hotspot mutations, copy number variations (CNV), mRNA expression, and protein expression using reverse-phase protein array (RPPA).
- Comparison of paired melanoma brain and extracranial metastases from surgically resected tumors.
Main Results:
- Mutations in BRAF and NRAS were concordant between paired tumors.
- Global patterns of CNV, mRNA, and protein expression were largely similar.
- Brain metastases exhibited increased expression of activated PI3K/AKT pathway proteins.
Conclusions:
- Melanoma brain metastases have distinct molecular characteristics, particularly in the PI3K/AKT pathway.
- The PI3K/AKT pathway represents a promising therapeutic target for melanoma brain metastases.
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