Cancer Hijacks Enzyme Substrate Mutations to Facilitate Tumorigenesis

项目摘要 遗传信息编码生活事件，包括疾病相关的变化和癌症治疗的提示。 一项艰巨的任务是解码遗传信息。一种常见的方法是调查基因变化是否 与肿瘤发生有关。已经致力于确定关键基因 扩增/缺失/融合事件和阐明热突变相关的酶变化和相互作用组 变化然而，酶上的突变仅占总突变景观的一小部分， 大多数非酶突变的含义仍然不清楚。为此，我们开发了一种算法， 为了挖掘靶向未充分研究的非酶突变的关键酶底物基序的获得或丢失， TCGA数据库，通过它可以改变关键酶的功能。作为一项原理性研究，使用 我们已经在癌症中鉴定了1，792个突变，这些突变导致AGC激酶的新基序丢失。这些 突变在结肠癌和食管癌中更丰富，更可能影响细胞信号传导途径。 更重要的是，我们验证了突变后的一个命中BUD 13可以通过一个AGC绕过其磷酸化。 激酶GRK 6，这些磷酸化缺陷的癌性BUD 13突变通过激酶GRK 6获得致癌性 通过提高mTORC 1信号来促进结肠癌的生长。在这份提案中，我们将系统地 鉴定所有表征的酶基序的第一个突变景观，并使用 一个实验管道，我们有专业知识。我们还将研究新的治疗方向相关 在体外细胞培养模型和体内细胞培养模型中， 临床前动物模型。我们希望我们的研究将为突变癌症劫持提供新的见解， 促进肿瘤发生，具有患者分层和癌症治疗的潜力。

PROJECT ABSTRACT Genetic information codes for life events including disease associated changes and hints for cancer treatments. A daunting task is to decode genetic information. A common approach is to investigate whether genetic changes in cancer are associated with tumorigenesis. Efforts have been devoted to identifying key gene amplification/deletion/fusion events and elucidating hot mutation-associated enzymatic changes and interactome changes. However, mutations on enzymes only account for a small portion of total mutational landscape and meanings of the majority of non-enzyme mutations remain unclear. To this end, we have developed an algorithm to mine the gain or loss of key enzyme substrate motifs targeting the understudied non-enzyme mutations from TCGA database, through which key enzyme functions can be altered. As a proof-of-principle study, using this approach we have identified 1,792 mutations in cancer that a new motif for the AGC kinases is lost. These mutations are more enriched in colon and esophageal carcinoma to more likely affect cellular signaling pathways. More importantly, we validated that one hit, BUD13, upon mutation can bypass its phosphorylation by one AGC kinase GRK6, through which these cancerous BUD13 mutations deficient in phosphorylation gain oncogenicity to promote colon cancer growth through elevating the mTORC1 signaling. In this proposal, we will systematically identify the first mutational landscape for all characterized enzyme motifs and further validate important hits using an experimental pipeline that we have expertise on. We will also examine new therapeutic directions associated with both WT- and mutant-BUD13 expressing colon cancer in both in vitro cell culture models and in vivo preclinical animal models. We hope that our study will provide novel insights for mutations cancer hijacks to promote tumorigenesis with the potential for patient stratification and cancer treatment.