Abstract 4304: MMP-9 as a marker of response to treatment with B-Raf inhibitors in cutaneous melanoma

Abstract

Abstract Malignant melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signaling pathways are constitutively activated through multiple mechanisms. Although, at present it has been demonstrated that the treatment with B-Raf enzyme inhibitors improve survival of melanoma patients, still these patients may relapse or become resistant to treatment. Therefore, there is a need to identify novel factors involved in melanoma development and/or progression. Matrix metalloproteinases (MMP) have been regarded as critical molecules in promoting tumor cell metastasis. Prognostic and diagnostic significance of MMP-9 overexpression has been shown in several cancer types. However, their role in melanoma was not fully investigated. Thus, we hypothesized that MMP-9 overexpression in melanoma may be involved in transformation and act as a prognostic biomarker. On this light, MMP-9 circulating levels, and MMP-9 gelatinase activity were measured by ELISA and zymography in a total of 148 melanoma samples with and without BRAFV600E mutation compared to healthy controls. The results showed that highest circulating levels of MMP-9 and MMP-9 activity were associated with advanced stages of disease. We have also demonstrated that higher levels of MMP-9 were detected among melanoma samples harboring BRAFV600E mutation compared to those BRAFWT. We further investigated if MMP-9 may be associated with acquired resistance to B-Raf inhibitors, such as Dabrafenib. Functional in vitro experiments were performed using commercial available melanoma cell lines. The results showed that MMP-9 was down-regulated in melanoma cells after treatment with Dabrafenib. While, higher MMP-9 expression levels were observed in the resistant clones compared to those detected in the parental cells. Intriguingly, similar trend was observed for pERK expression. Overall, these data indicate that MMP-9 may play a role for the evaluation of response to treatment with B-Raf inhibitors in melanoma patients. Note: This abstract was not presented at the meeting. Citation Format: Saverio Candido, Grazia Malaponte, Rossella Salemi, Franca Maria Pezzino, Aurora Scalisi, James A. McCubrey, Massimo Libra. MMP-9 as a marker of response to treatment with B-Raf inhibitors in cutaneous melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4304. doi:10.1158/1538-7445.AM2015-4304