MYC 家族癌蛋白在>30%的人类肿瘤中异常高表达，参与调控肿瘤发生发展的几乎所有关键过程。在模式动物上干预MYC的表达/活性，可显著甚至完全抑制肿瘤的发生和发展，提示MYC是肿瘤治疗的有效靶点。然而，直接针对转录因子MYC的靶向抑制剂研发到目前为止尚未成功。因此，寻找与MYC存在协同致死关系的关键靶点并据此研发药物已成为间接干预MYC的理想替代途径。代谢异常是肿瘤的新特征之一，为肿瘤细胞生长提供能量和物质基础。通过筛选2752个代谢酶和转运体基因，我们新发现苹果酸酶2、谷氨酰胺果糖-6-磷酸转氨酶1和Nudix水解酶1等代谢靶点的失活与MYC形成显著的协同致死效应。本研究拟采用细胞分子生物学、代谢组学、模式动物等技术方法，进一步探讨干预这些关键代谢靶点协同MYC选择性杀死肿瘤细胞的分子机制，及相应代谢通路异常对肿瘤发生发展进程的影响，以期从代谢角度为MYC过表达肿瘤的治疗提供新思路。

Deregulation of MYC occurs in >30% of human cancers, and is consistently associated with abnormally high levels of Myc protein, which activates target genes involved in almost every aspect of oncogenesis. Inhibition of MYC results in blockade in tumorigenesis and induces even tumor regression in multiple tumor models, suggesting that therapeutic efforts aimed at inhibiting MYC should have an important clinical relevance. However, direct pharmacological targeting of Myc transcription factors has not been achieved thus far. Identification of alternative strategies based on the concept of synthetin letality has therefore become a promising approch in reaching selective MYC inhibition. Deregulated metabolism is one of the emering cancer hallmarks, providing tumor cells energy and building blocks to sustain their unstrained proliferation. Through screening 2752 genes encoding metabolic enzymes and transporters, we identify multiple critical metabolic targets, including malic enzyme 2 (ME2), glutamine-fructose-6-phosphate aminotransferase 1 (GFPT1) and nudix hydrolase 1 (NUDT1), constitute a synthetic lethal interaction with oncogenic MYC. In the current study, we will continue to investigate the potential mechnisms involved in through techenologies ranging from molecular cell biology, metabolomics and animal modeling, with an aim to achieve selective targeting of oncogenic MYC by inhibition of key metabolic pathways.