Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11.

Despite advances in developing specific inhibitors to BRAF mutant melanomas, to date there are no effective therapies for tumors bearing NRAS mutations, present in approximately 15–20% of human melanomas. Here, we extend earlier studies, demonstrating that the small molecule BI-69A11 inhibits the growth of melanoma cell lines in vitro and in vivo. Gene expression microarray analysis of BI-69A11-responsive melanoma cells revealed the induction of interferon- and cell death-related genes that were associated with responsiveness to BI-69A11. Strikingly, the administration of BI-69A11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated Nras and a deletion of the Ink4a gene (Nras(Q61K)::Ink4a−/−). Biweekly administration of BI-69A11 starting at 10 weeks or as late as 24 weeks after the induction of mutant Nras expression inhibited melanoma development (100% and 36%, respectively). BI-69A11 treatment did not inhibit the development of histiocytic sarcomas, which comprise about 50% of the tumors in this model. Immunofluorescent staining analyses of CD45 revealed increased levels of immune cell infiltration in BI-69A11–treated tumors. Gene expression profiling of BI-69A11-resistant Nras(Q61K)::Ink4a−/− tumors revealed the upregulation of functional gene networks associated with the cytoskeleton, DNA damage response, and small molecule transport. The ability to attenuate development of NRAS mutant melanomas by BI-69A11 even when administered at a late stage of the tumor development, support its further development and clinical assessment.