Loss of the tumor suppressor NF1 leads to activation of RAS effector pathways, which are therapeutically targeted by inhibition of mTOR (mTORi) or MEK (MEKi). However, therapeutic inhibition of RAS effectors leads to the development of drug resistance and ultimately disease progression. To investigate molecular signatures in the context of NF1 loss and subsequent acquired drug resistance, we analyzed the exomes, transcriptomes, and kinomes of Nf1-mutant mouse tumor cell lines and derivatives of these lines that acquired resistance to either MEKi or mTORi. Biochemical comparisons of this unique panel of tumor cells, all of which arose in Nf1+/− mice, indicate that loss of heterozygosity of Nf1 as an initial genetic event does not confer a common biochemical signature or response to kinase inhibition. Although acquired drug resistance by Nf1-mutant tumor cells was accompanied by altered kinomes and irreversibly altered transcriptomes, functionally in multiple Nf1-mutant tumor cell lines, MEKi resistance was a stable phenotype, in contrast to mTORi resistance, which was reversible. Collectively, these findings demonstrate that Nf1-mutant tumors represent a heterogeneous group biochemically and undergo broader remodeling of kinome activity and gene expression in response to targeted kinase inhibition.

中文翻译：

---

Nf1 突变肿瘤在抑制 mTOR 或 MEK 后经历转录组和激酶组重塑

肿瘤抑制因子 NF1 的缺失导致 RAS 效应通路的激活，这些通路通过抑制 mTOR (mTORi) 或 MEK (MEKi) 进行治疗。然而，对 RAS 效应子的治疗性抑制会导致耐药性的发展并最终导致疾病进展。为了研究 NF1 缺失和随后获得性耐药性背景下的分子特征，我们分析了 Nf1 突变小鼠肿瘤细胞系的外显子组、转录组和激酶组，以及这些获得 MEKi 或 mTORi 耐药性的细胞系的衍生物。这种独特的肿瘤细胞组的生化比较，所有这些都出现在 Nf1+/- 小鼠中，表明作为初始遗传事件的 Nf1 杂合性的丧失不会赋予共同的生化特征或对激酶抑制的反应。尽管 Nf1 突变肿瘤细胞的获得性耐药伴随着激酶组的改变和不可逆的转录组改变，但在多个 Nf1 突变肿瘤细胞系的功能上，MEKi 耐药是一种稳定的表型，而 mTORi 耐药是可逆的。总的来说，这些发现表明 Nf1 突变肿瘤在生化上代表了一个异质组，并且响应靶向激酶抑制而经历更广泛的激酶组活性和基因表达重塑。