Abstract 1535: Increasing integrin function from within the cell sensitizes melanomas to chemotherapy

Abstract Metastatic melanoma is an aggressive skin disease for which there are no effective therapies. Emerging evidence indicates that melanomas can be sensitized to chemotherapy by increasing integrin function. Current therapies work by targeting integrins from outside the cell, resulting in complete gains or losses of integrin function that lead to mechanism-based toxicities. An attractive alternative approach would be to target proteins, such as vinculin, that associate with the integrin cytoplasmic domains and regulate its ligand binding properties. Here we report that a novel reagent, denoted vinculin activating peptide or VAP, increases integrin activity from within the cell, as measured by elevated: (1) active integrins on the cell surface, (2) adhesion of cells to extracellular matrix ligands, (3) numbers of cell-matrix adhesions, and (4) downstream signaling. These effects are dependent on both integrins and a key regulatory residue A50 in the vinculin head. We further show that VAP enhances integrin function independent of both its mode of delivery and the melanoma cell type tested. Furthermore, VAP dramatically increases the sensitivity of melanomas to chemotherapy in clonal growth assays and in vivo mouse models of melanoma. Finally, we demonstrate that the increase in chemosensitivity results from increases in p53-dependent DNA damage-induced apoptosis. Collectively these findings demonstrate for the first time that integrin function can be manipulated from within the cell and validate integrins as a new strategy for the treatment of chemoresistant melanomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1535. doi:10.1158/1538-7445.AM2011-1535