Abstract 2567: Expression of BRAF splice variants lacking the catalytic domain predicts dacarbazine response in advanced melanoma

Abstract

Abstract BACKGROUND: Metastatic melanomas respond poorly to chemotherapy. The aim of this single institution study was to correlate BRAF and NRAS mutation status to dacarbazine (DTIC) response and outcome in metastatic melanomas. METHODS: Snap-frozen tissue samples were obtained from 85 malignant melanoma deposits. Seventy-five of these were from patients evaluable for response to dacarbazine treatment, and BRAF and NRAS status was correlated to treatment outcome. In addition, cell culture studies were performed, evaluating the effect of BRAF/NRAS status on dacarbazine sensitivity. RESULTS: We identified two BRAF splice variants lacking key parts of the catalytic domain (exon 12-15 and exon 14-15, respectively). Splice expression and BRAF V600E mutation status were mutually exclusive (p=0.006). All patients obtaining an objective response to chemotherapy expressed splice variants (p=0.014 and p=0.043 at 6 and 12 weeks, respectively). siRNA-mediated BRAF knockdown increased dacarbazine sensitivity in a melanoma cell line wt for BRAF (SBcl2) but not in SK-MEL 28, harbouring BRAF V600E. No correlation between BRAF or NRAS mutation status and treatment response was recorded. CONCLUSION: Our findings suggest that BRAF plays a key role conferring resistance to dacarbazine treatment in metastatic melanomas and the del 12-15 or del 14-15 splice variants to have BRAF antagonizing effects. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2567.