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Systematic analysis uncovers SYK dependency in NF1LoF melanoma cells
bioRxiv - Cancer Biology Pub Date : 2022-09-21 , DOI: 10.1101/2022.03.06.483170
Cara Abecunas , Christopher Whitehead , Elizabeth Ziemke , Douglas G. Baumann , Christy Frankowski-McGregor , Judith Sebolt-Leopold , Mohammad Fallahi-Sichani

The loss of function (LoF) of NF1 is the third most frequent mutation that drives hyperactivated RAS and tumor growth in >10% of melanomas. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. Here, we perform a targeted kinase inhibitor screen and identify a tool compound, named MTX-216, to be highly effective in blocking NF1LoF melanoma cells. Single-cell analysis links drug-induced cytotoxicity to effective co-suppression of proliferation marker Ki-67 and the ribosomal S6 phosphorylation, an integrator of multiple RAS-mediated signaling pathways. Using a combination of kinome selectivity assay, transcriptomic analysis, and genetic experiments, we find the anti-tumor efficacy of MTX-216 to be dependent on its ability to inhibit not only PI3K (its nominal target) but also SYK, and suppression of a group of genes that regulate mitochondrial electron transport chain and whose expression is associated with poor survival in NF1LoF melanoma patients. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown show favorable effects. These studies provide a path to exploit SYK dependency to selectively block NF1LoF melanoma cells.

中文翻译:

系统分析揭示了 NF1LoF 黑色素瘤细胞中的 SYK 依赖性

NF1 的功能丧失 (LoF) 是第三个最常见的突变,它在 >10% 的黑色素瘤中驱动过度活化的 RAS 和肿瘤生长。然而, NF1 LoF黑色素瘤细胞对单独的 MEK、ERK 或 PI3K/mTOR 抑制剂没有表现出一致的敏感性。在这里,我们进行了靶向激酶抑制剂筛选,并确定了一种名为 MTX-216 的工具化合物,可高效阻断 NF1 LoF黑色素瘤细胞。单细胞分析将药物诱导的细胞毒性与增殖标志物 Ki-67 和核糖体 S6 磷酸化(多种 RAS 介导的信号通路的整合剂)的有效共抑制联系起来。结合激酶组选择性测定、转录组分析和遗传实验,我们发现 MTX-216 的抗肿瘤功效取决于其抑制 PI3K(其名义目标)和 SYK 的能力,以及抑制一组调节线粒体电子传递链的基因,其表达与 NF1 LoF中的低存活率有关黑色素瘤患者。此外,靶向 MEK 或 PI3K/mTOR 的抑制剂与独立的 SYK 激酶抑制剂或 SYK 敲低的组合显示出良好的效果。这些研究提供了一条利用 SYK 依赖性选择性阻断 NF1 LoF黑色素瘤细胞的途径。
更新日期:2022-09-22
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