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损伤的反应中很重要。最近的研究结果表明，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敲低鉴定了编码SUMO活化酶（SAE）催化亚基的基因SAE 2，该基因与Myc超活化具有最强的合成致死相互作用。类似地，编码SUMO化酶的基因被发现对于KRas依赖性肿瘤发生至关重要。基于这些发现，我们假设SAE是开发Myc和KRas依赖性癌症的抗癌疗法的新靶点。本提案的首要目标是验证这一假设，并且通过我们发现对具有高Myc表达水平和/或KRas突变的癌细胞系具有选择性毒性的有效和特异性SAE抑制剂，使所提出的研究成为可能。我们建议研究具有Myc超活化和KRas突变的SUMO化的合成致死性的分子机制，以进一步验证SAE作为潜在的癌症治疗靶点。此外，我们还将研究结构-活性关系， 抑制剂与SAE相互作用并抑制其酶活性，并使用该信息指导抑制剂的进一步改进。这些研究可能会改善许多癌症的治疗，因为据估计，Myc的过表达导致了70%的人类癌症，而KRas在人类癌症中也经常突变。然而，Myc和KRas都已被证明难以抑制β-内酰胺酶。因此，拟定的研究可能会建立一种新的范式，以针对SAE开发新型癌症治疗。

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.