The relevance of BRAF G469A mutation in determining the response to therapy in metastatic melanoma

Letizia Porcelli,Gabriella Guida,Michele Guida,Anna Ferretta,Tiziana Cocco,Imma Maida,Amalia Azzariti,Stefania Guida,Claudia Grieco,Stefania Tommasi,Sabino Strippoli,D Stolfa ,Anna Elisa Quatrale ,Rosa Maria Iacobazzi

doi:10.1186/1479-5876-13-s1-p3

Abstract

Background BRAF G469A is a missense mutation within exon 11 of the BRAF gene resulting in a constitutively active state of the enzyme responsible also for the protein localization to the mitochondria. The BRAF G469A mutation, frequently recovers in lung cancer, is rare in melanoma and uncertain is its association with a more aggressive disease. BRAF G469A mutation is frequently associated to MAP kinase cascade signaling activation, however no evidence currently exists about its role in determining sensitivity/resistance to BRAF inhibitors vemurafenib or dabrafenib. In our Institute, a patient with metastatic melanoma (MM) was treated with fotemustine, however the disease progressed. From patient biopsy, a new metastatic melanoma cell line has been established and named Mo-1. Here, we investigated the sensitivity of Mo-1 cells to vemurafenib and abraxane, both already approved for the treatment of melanoma carrying BRAF V600 mutations, comparing it with that found in MM cells wild type for BRAF or mutated in V600. Furthermore, a biomarker for the response to abraxane is hypothesized.

Highlights

BRAF G469A is a missense mutation within exon 11 of the BRAF gene resulting in a constitutively active state of the enzyme responsible for the protein localization to the mitochondria
BRAF G469A mutation is frequently associated to MAP kinase cascade signaling activation, no evidence currently exists about its role in determining sensitivity/resistance to BRAF inhibitors vemurafenib or dabrafenib
We investigated the sensitivity of Mo-1 cells to vemurafenib and abraxane, both already approved for the treatment of melanoma carrying BRAF V600 mutations, comparing it with that found in MM cells wild type for BRAF or mutated in V600

Summary

Background

BRAF G469A is a missense mutation within exon 11 of the BRAF gene resulting in a constitutively active state of the enzyme responsible for the protein localization to the mitochondria. The BRAF G469A mutation, frequently recovers in lung cancer, is rare in melanoma and uncertain is its association with a more aggressive disease. BRAF G469A mutation is frequently associated to MAP kinase cascade signaling activation, no evidence currently exists about its role in determining sensitivity/resistance to BRAF inhibitors vemurafenib or dabrafenib. In our Institute, a patient with metastatic melanoma (MM) was treated with fotemustine, the disease progressed. A new metastatic melanoma cell line has been established and named Mo-1. We investigated the sensitivity of Mo-1 cells to vemurafenib and abraxane, both already approved for the treatment of melanoma carrying BRAF V600 mutations, comparing it with that found in MM cells wild type for BRAF or mutated in V600. A biomarker for the response to abraxane is hypothesized

Materials and methods

Results

Conclusion