Abstract 3495: Targeted therapies in melanoma – in vitro effects of single and combined drug treatment

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Malignant melanoma is one of the most rapidly increasing malignancies in Caucasian populations. So far, curative treatment is achieved only by surgical resection at an early stage, while the prognosis in cases with disseminated melanoma is poor, and we lack predictive tools to identify the few patients who respond to existing chemotherapy. Promising clinical trials of targeted therapies are ongoing, however, it is already clear that drug resistance will be a clinical reality also for these new therapies. Thus, novel predictive markers are urgently needed to identify responders to different types of therapy in melanoma. The aim of the study is to unravel molecular mechanisms and pathways underlying resistance to new therapies in melanoma. We are studying the effects of a set of MAPK and PI3K pathways inhibitors in melanoma cell lines that are wildtype or have different mutations/deletions in genes affecting these pathways (BRAF, NRAS, PTEN etc.). Cells are exposed to single drugs as well as combinations of inhibitors and/or chemotherapeutic agents. Our results have shown that there is a wide range of sensitivity to the BRAF inhibitor PLX4720 among BRAF mutated cell lines, with IC50 values varying from 0.3 µM to 30 µM. We are investigating the underlying mechanisms causing this variation in sensitivity to the drug. Using gene expression profiling of a clinical material, we have identified several candidate genes that may predict response to DNA alkylating agents dacarbazine and temozolomide. The expression of some of these genes can be affected by PLX4720, and their potential relevance for response to different treatments is currently tested in vitro. 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 3495. doi:10.1158/1538-7445.AM2011-3495