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Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1LoF 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 cosuppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The antitumor 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 patients with NF1LoF melanoma. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1LoF melanoma cells., Significance: A kinase inhibitor screen identifies SYK as a targetable vulnerability in melanoma cells with NF1 loss of function., (©2022 The Authors; Published by the American Association for Cancer Research.)