Azzariti A.

COCCO, Tiziana Maria

Ferretta A

Grieco C

Guida M

Guida S

GUIDA, Gabriella

Iacobazzi RM

MAIDA, Immacolata

Porcelli L

Quatrale AE

Stolfa D

Strippoli S

Tommasi S

Journal of Translational Medicine

English

Archivio istituzionale della ricerca - Università di Bari

POSTER PRESENTATION Open AccessThe relevance of BRAF G469A mutation indetermining the response to therapy inmetastatic melanomaLetizia Porcelli1, Gabriella Guida2, Tiziana Cocco3, Anna E. Quatrale1, Rosa M Iacobazzi1, Diana A Stolfa2,Imma Maida1, Anna Ferretta3, Claudia Grieco2, Stefania Guida2, Sabino Strippoli4, Stefania Tommasi1,Michele Guida4, Amalia Azzariti1*From Melanoma Bridge Meeting 2014Naples, Italy. 03-06 December 2014BackgroundBRAF G469A is a missense mutation within exon 11 ofthe BRAF gene resulting in a constitutively active stateof the enzyme responsible also for the protein localiza-tion to the mitochondria. The BRAF G469A mutation,frequently recovers in lung cancer, is rare in melanomaand uncertain is its association with a more aggressivedisease. BRAF G469A mutation is frequently associatedto MAP kinase cascade signaling activation, however noevidence currently exists about its role in determiningsensitivity/resistance to BRAF inhibitors vemurafenib ordabrafenib. In our Institute, a patient with metastaticmelanoma (MM) was treated with fotemustine, howeverthe disease progressed. From patient biopsy, a newmetastatic melanoma cell line has been established andnamed Mo-1. Here, we investigated the sensitivity ofMo-1 cells to vemurafenib and abraxane, both alreadyapproved for the treatment of melanoma carrying BRAFV600 mutations, comparing it with that found in MMcells wild type for BRAF or mutated in V600. Further-more, a biomarker for the response to abraxane ishypothesized.Materials and methodsWe tested the sensitivity of Mo-1 (BRAF G469A), HBLand LND-1 (BRAF wild type), MBA72 and Hmel-1(BRAF V600) to abraxane and vemurafenib by MTTcytotoxicity assay. In addition, cellular effectors wereinvestigated by ELISA kits, western blotting and flowcytometry.ResultsThe exposure to vemurafenib leads to a progressiveinhibition of proliferation however, the concentrationsutilized are high and similar to those utilized in MMmodels constitutively resistant to BRAF inhibitors. Thus,the BRAF mutation G469A confers resistance to vemur-afenib also confirmed by the partial response obtainedwhen the patients was treated with the drug. The cellu-lar effector responsible for the resistance might be theactivation of Erk1/2.The binding of BRAF G469A to the outer mitochon-drial membrane suggested to evaluate the mitochondriafunctionality in Mo-1 cells. An high production of ATPand the release of lactate were evident.Finally, abraxane, which induces mitochondria-mediatedapoptosis, strongly reduced proliferation in Mo-1 cells.Possible biomarker responsible for this response is thevery low expression level of PMEL17, transcriptionallyregulated by MITF, which is known to be negativelyinvolved in determining the activity of taxanes.ConclusionThus, the mutation BRAF G469A in patients with MMshould be related to a weak effectiveness of therapy withBRAF inhibitors and a promising therapeutic approachmay be with abraxane.Authors’ details1Clinical Experimental Oncology Laboratory, Istituto Tumori Giovanni Paolo II,Bari, Italy. 2Dept. of Basic Medical Sciences, Neurosciences and Sense Organs,1Clinical Experimental Oncology Laboratory, Istituto Tumori Giovanni Paolo II,Bari, ItalyFull list of author information is available at the end of the articlePorcelli et al. Journal of Translational Medicine 2015, 13(Suppl 1):P3http://www.translational-medicine.com/content/13/S1/P3© 2015 Porcelli et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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

https://ricerca.uniba.it/bitstream/11586/139865/2/The%20relevance%20of%20BRAF%20G469A%20mutation%20in%20determining%20the%20response%20to%20therapy%20in%20metastatic%20melanoma.pdf

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

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Archivio istituzionale della ricerca - Università di Bari