PDF(Pubmed)
Abstract：
Malignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity. Trp53 loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.
摘要：
恶性外周神经鞘瘤（MPNSTs）是化疗耐药的肉瘤，是1型神经纤维瘤病（NF1）死亡的主要原因。尽管NF1相关的MPNST来自神经c细胞起源，它们也表现出瘤内异质性。TP53突变与MPNSTs的生存率显著降低有关，然而,在NF1缺乏的情况下,TP53介导的治疗应答的潜在机制尚不清楚.我们评估了两种常见改变基因的作用，MET和TP53，在临床前MPNST小鼠模型的kinome重编程和细胞分化中。我们先前表明MET扩增发生在人类MPNST进展的早期，并且Trp53丢失消除了MET成瘾，导致MET抑制剂耐药。在这里，我们证明了一种新的治疗抵抗机制，即p53改变MET稳定性，本地化,和下游信号导致kinome重编程和谱系可塑性。Trp53丢失还导致RAS/ERK向AKT信号传导的转变,并增强对MEK和mTOR抑制的敏感性。为了回应MET,MEK和mTOR抑制,我们观察到Trp53缺陷系中关键分化基因的广泛和异质激活,提示Trp53缺失也影响MPNSTs的谱系可塑性.这些结果证明了p53丢失通过kinome重编程和表型灵活性改变MPNSTS中MET依赖性和治疗抗性的机制。
