Loss of NF1 in melanoma confers sensitivity to SYK kinase inhibition.

NF1 loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1-LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1-LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single cell analysis indicated that drug-induced cytotoxicity was linked to effective co-suppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The anti-tumor efficacy of MTX-216 was dependent on its ability to inhibit not only PI3K, its nominal target, but also SYK. MTX-216 suppressed expression of a group of genes that regulate mitochondrial electron transport chain and are associated with poor survival in NF1-LoF melanoma patients. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1-LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1-LoF melanoma cells.