Abstract 4215: Integrin-dependent mechanisms for sensitizing melanomas to chemotherapy

Abstract

Abstract BRAF is mutated in 50-70% of human melanomas, resulting constitutive activation of the MEK-ERK1/2 signal transduction pathway and resistance to apoptosis. Agents that target the oncogenic BRAF signaling pathway are revolutionizing the treatment of metastatic melanoma. However, it is already evident that there is both intrinsic and acquired resistance to this class of compounds suggesting that combinatorial therapies may be needed to combat melanoma resistance. We recently described a novel compound, denoted vinculin activating peptide (VAP) that engages defective integrins with the extracellular matrix and consequently sensitizes melanomas to chemotherapy. VAP is relatively large and the minimal sequences required for the sensitization of melanomas to chemotherapy are not known. In this study, we investigated the smallest domains of VAP that are required for its chemosensitizing effects. Here, we report that VAP contains three small domains, termed vinculin binding sites (VBSs) which are sufficient to bind the integrin-associated protein, vinculin and sensitize melanoma cells to chemotherapeutics. Out of the three VBSs within VAP, VBS3 exhibits stronger binding to vinculin and increases cell-matrix adhesion and focal adhesion number to a greater extent. Furthermore, VBS3 enhances melanoma sensitivity to chemotherapy more than VBS1 or VBS2. The residues of VBS3 required for the sensitization of melanomas have been investigated and suggest that divergent residues are important for chemosensitization. Collectively these data suggest that small molecule mimetics of VBS3 would be an ideal therapy to overcome the resistance of metastatic melanomas to chemotherapeutic agents. 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 4215. doi:1538-7445.AM2012-4215