Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma
Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma
复制标题
DOI：
10.1126/scitranslmed.aay2163
复制
发表时间：
2020-06-10
影响因子：
17.1
通讯作者：
Linares, Laetitia K.
中科院分区：
文献类型：
--
作者：
Cisse, Madi Y.;Pyrdziak, Samuel;Linares, Laetitia K.
高分化和去分化脂肪肉瘤（lps）的特征是MDM2癌基因的系统性扩增，该基因编码p53通路的一个关键负调控因子。在LPS中MDM2过表达而保留野生型p53的分子机制尚不清楚。在这里，我们发现染色质结合的MDM2不依赖p53的代谢功能在LPS中被加剧，并介导对丝氨酸代谢的依赖，从而维持核苷酸合成和肿瘤生长。用MDM2-p53相互作用的药理学抑制剂Nutlin-3A处理LPS细胞，稳定了p53，但出乎意料的是，通过增加丝氨酸向染色质的募集，增强了MDM2介导的丝氨酸代谢控制，这可能解释了这类MDM2抑制剂临床疗效不佳的原因。相比之下，SP141（一种独特的MDM2抑制剂，可触发其降解，或干扰新生丝氨酸合成）对染色质结合MDM2的遗传或药理学抑制，在体外和临床相关的患者来源的异种移植模型中都会损害LPS的生长。我们的数据表明，靶向MDM2在丝氨酸代谢中的功能代表了LPS的潜在治疗策略。
Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS.