Abstract 711: Understanding the Mechanisms of Resistance to BRAF Inhibitors in Melanoma

The presence of activating BRAF mutations in approximately 50% of melanomas, the majority of which are BRAFV600E, has prompted the development of selective BRAF inhibitors for targeted therapy. Pre-clinical data using multiple BRAF inhibitors and results from recent clinical trials using PLX4032 validate the effectiveness of this treatment strategy and offers hope to patients suffering from this deadly disease. However, similar to other malignancies, therapy with BRAF inhibitors is effective in only a subset of patients and even if an initial effective response is observed, tumors eventually develop resistance and patients relapse. We recently reported that acquired resistance to BRAF inhibitors can be mediated by non-genetic mechanisms through rewiring of their signaling pathways and this is mediated by a RAF kinase switch and increased PI3K-dependent survival. However, as melanoma is a highly heterogeneous disease, we anticipate that multiple mechanisms can be associated with acquired resistance to BRAF and/or MEK inhibitors. Also, the mechanisms of intrinsic resistance can be different from those underlying acquired resistance. Here we report that melanoma cells which harbor the BRAFV600E mutation and express PTEN have low levels of phospho-AKT and are sensitive to BRAF inhibitors. In contrast, BRAFV600E mutant melanoma cell lines that do not express PTEN have higher levels of phospho-AKT and are less sensitive to BRAF inhibitors. Co-targeting PI3K and mutant BRAF in melanoma cells that lack functional PTEN sensitizes them to the combination strategy. Our studies suggest that the presence or absence of functional PTEN can modulate response to inhibitors of the MAPK pathway and warrant further evaluation of combination strategies to treat melanomas refractory to BRAF inhibitors. 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 711. doi:10.1158/1538-7445.AM2011-711