SUMO modification and cancer therapy

描述(由申请人提供)：小泛素样修饰物(SUMO)家族的翻译后修饰在肿瘤发生和细胞对DNA损伤的反应中非常重要。最近的发现表明，由Myc和KRAS驱动的关键致癌途径依赖于或依赖于SUMO化。在一项研究中，全基因组siRNA敲除发现编码相扑激活酶(SAE)催化亚基SAE2的基因与Myc过度激活具有最强的合成致死性相互作用。同样，编码糖基化酶的基因被发现在KRAS依赖的肿瘤发生中起关键作用。基于这些发现，我们假设SAE是为依赖Myc和KRAS的癌症开发抗癌疗法的新靶点。这项提议的总体目标是检验这一假说，我们发现了有效和特异的SAE抑制剂，这些抑制剂对具有高Myc表达水平和/或KRAS突变的癌细胞株具有选择性毒性，从而使拟议的研究成为可能。我们建议研究伴随Myc高激活和KRAS突变的SUMO化合成致命性的分子机制，以进一步验证SAE作为潜在的癌症治疗靶点。此外，我们将研究结构-活性关系如何 抑制剂与SAE相互作用并抑制其酶活性，并利用这一信息指导进一步改进抑制剂。这些研究可能会改善许多癌症的治疗，因为Myc的过度表达估计导致了70%的人类癌症，而且KRAS在人类癌症中也经常发生突变。然而，Myc和KRAS都被证明很难在药理上抑制。因此，拟议的研究可能会建立一个新的范例，以SAE为目标开发新的癌症治疗方法。

DESCRIPTION (provided by applicant): Post-translational modifications by the small ubiquitin-like modifier (SUMO) family are important in oncogenesis and cellular response to DNA damage. Recent findings indicate that the key oncogenic pathways driven by Myc and KRas are dependent on, or addicted to, SUMOylation. In one study, genome-wide siRNA knockdown identified the gene encoding the catalytic subunit of the SUMO activating enzyme (SAE), SAE2, as having the strongest synthetic lethal interaction with Myc hyperactivation. Similarly, genes encoding the SUMOylation enzymes were found to be critical for KRas-dependent tumorigenesis. Based on these findings, we hypothesize that the SAE is a novel target for developing anti-cancer therapeutics for cancers that are Myc-and KRas-dependent. The over-arching goal of this proposal is to test this hypothesis, and the proposed studies are enabled by our discovery of potent and specific SAE inhibitors that have selective toxicity to cancer cell lines that have high Myc-expression levels and/or KRas mutation. We propose to investigate the molecular mechanisms underlying the synthetic lethality of SUMOylation with Myc hyperactivation and KRas mutations in order to further validate the SAE as a potential cancer therapeutic target. In addition, we will investigate the structure-activity relationship of how the inhibitors interact with the SAE and inhibit its enzymatic activity, and use this information to guide further improvement of the inhibitors. These studies could potentially improve treatment of many cancers, as overexpression of Myc is estimated to contribute to 70% of all human cancers, and KRas is also frequently mutated in human cancers. However, both Myc and KRas have proven difficult to inhibit pharmacologically. Thus, the proposed studies will likely establis a new paradigm to target the SAE for the development of novel cancer therapies.