Abstract 4326: Responses of a direct in vivo xenograft model of melanoma to MKK1/2 inhibitor

Abstract

Abstract Metastatic melanoma is the most aggressive form of skin cancer, accounting for 80% of skin cancer deaths due to its high resistance to conventional chemotherapy. Recent studies have shown that metastatic melanomas are susceptible to targeted therapeutics using inhibitors of BRAF or MKK1/2 protein kinases. Here, we study the effect of the MKK1/2 inhibitor, AZD6244, on a direct in vivo xenograft model of melanoma, as well as the effect of MKK1/2 inhibitors, AZD6244 and CI1040 and the BRAF-V600E inhibitor, PLX4720, on established cell lines and cells from direct in vivo xenografts grown in 2D culture. Treatment with CI1040 elicited strong cell death responses in six of nine established melanoma cell lines, reaching 65-80% apoptosis after 48 h. Xenografts of established melanoma cell lines were also responsive to MKK1/2 inhibitor, showing suppressed tumor growth in animals treated with CI1040 in the presence or absence of temozolomide. Likewise, MKK1/2 inhibitor suppressed tumor growth in a direct in vivo xenograft model of melanoma, where tumors harboring BRAF-V600E mutations showed complete growth inhibition in response to AZD6244. One tumor harboring BRAF-WT showed partial growth suppression with AZD6244 alone, but complete suppression was achieved when AZD6244 was combined with temozolomide. Unexpectedly, cells derived from direct in vivo xenografts and grown in 2D culture showed relatively low apoptotic responses when treated with MKK1/2 or BRAF inhibitors. The results suggest that tumor and cell growth conditions might influence mechanisms underlying the oncogene addiction response to constitutive activation of the BRAF/MKK/ERK pathway. 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 4326. doi:10.1158/1538-7445.AM2011-4326