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Loss of NF1 in melanoma confers sensitivity to SYK kinase inhibition.
Cancer Research 2022 November 22
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.
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