Abstract 4214: Identifying cell surface receptor VAP targets to sensitize melanoma to chemotherapy

Abstract

Abstract Melanoma accounts for 79% of all skin cancer deaths. The incidence rate has doubled throughout the past three decades, while the survival rate remains consistently low. Melanoma is unusually lethal as it metastasizes early and is highly resistance to all available chemotherapeutics. The newest treatment utilizes a small inhibitor targeting the BRAF pathway, considering the BRAF V600E mutation occurs in 65% of clinical melanoma cases. Unfortunately, it is clear that there is both primary and acquired resistance to the drug. Recent studies demonstrate that engaging defective cell surface adhesion receptors known as integrins increases the sensitivity of melanoma to traditional DNA damaging agents. Our laboratory has identified a novel peptide denoted vinculin activating peptide (VAP) that increases integrin engagement from within the cell by targeting the integrin cytoplasmic binding partner, vinculin. Furthermore, VAP sensitizes melanoma to DNA damaging agents in vitro and in vivo. The goal of this project is to identify the cell surface target of VAP. Both α1and β3 integrins are highly over-expressed in melanoma, suggesting that VAP targets one or both of these defective integrins. To test this possibility, melanoma cells lacking β1 or β3 integrins were generated. In the absence of β1 integrins, VAP did not induce elevations in p53 levels or increase apoptosis in melanoma cell lines treated with cytotoxic agents. In addition, its ability to sensitize melanoma cells to therapeutics in biological assays was ablated. Furthermore, the β1 integrin-dependency of VAP's effect was confirmed by examining melanoma cells lacking β3 integrins. Ongoing experiments are testing the requirement for β1 integrin in mouse models of melanoma. Taken together, these findings suggest that β1 integrins are required for VAP to sensitize melanomas to chemotherapy agents. The successful completion of these studies will provide the mechanistic underpinning for a new class of therapeutics that sensitize melanomas to chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4214. doi:1538-7445.AM2012-4214