Targeting APOBEC3A-expressing cancer cells with ATR inhibitors

项目摘要 基因组不稳定是癌症的一个标志。一方面，癌细胞的基因组不稳定性促进了 肿瘤抑制基因的丢失和癌基因的激活。另一方面，基因组的不稳定性会导致癌症 对放射和化疗敏感的细胞。最近，“合成杀伤力”的概念已经被 成功地用于开发癌细胞的基因组不稳定性。例如，DNA修复缺陷 BRCA1/2缺陷细胞对PARP抑制剂高度敏感。在本申请中，我提出了一种新的合成方法 用ATR检查点激酶抑制剂靶向表达APOBEC3A的癌细胞的致死策略。我的 拟议的研究可能揭示ATR在应对APOBEC3A诱导的DNA损伤中的关键作用。 开发一种特定杀死表达APOBEC3A的癌细胞的策略将是靶向 癌症治疗。 我的职业目标是在一家领先的学院获得一个研究教员的职位，在那里我将剖析 APOBEC3A导致细胞基因组不稳定的机制。然而，我成功地过渡到 通过增加我在细胞生物学方面的专业知识，我在这一领域的独立性将大大增强。 在老鼠癌症模型中有新的训练机会的技术。正是凭借这些获得的技能，我将成为 能够研究ATR抑制剂是否可以用来特异性地靶向表达 APOBEC3A.这个项目的成功将因我所拥有的杰出合作者而大大增强 在我向独立过渡的整个过程中，他们聚集在一起为我提供建议。此外，例外的研究 MGH提供的环境和哈佛医学院区域拥有所有必要的资源 拟议的培训和研究研究所需的。K99/R00奖将为我提供 这一高级培训所需的保护时间，并允许我继续在 邹丽红博士的导师。我希望这一裁决所提供的保护时间将允许我澄清 ATR在高表达APOCBEC3A细胞中的作用及ATR抑制物(ATRI)是否可以 用于提高高水平APOBEC3A对癌细胞的合成杀伤力。在目标1中，我将阐明如何 ATR抑制可导致表达APOBEC3A的细胞死亡。在目标2中，我将确定目标是什么 人类细胞中的载脂蛋白BEC3A。最后，在目标3中，我将研究ATR抑制剂是否可以用于 特异性靶向表达APOBEC3A的癌细胞。 尽管我最近接受了生物化学和细胞生物学方面的培训，但我还需要1-2年的额外培训来 让自己成为一名独立的调查员。获得这一奖项不仅可以让我扩大我的 研究计划，但也确立了我作为癌症生物学领域主要研究员的地位

Project Summary Genomic instability is a hallmark of cancer. On one hand, genomic instability of cancer cells promotes loss of tumor suppressors and activation of oncogenes. On the other hand, genomic instability renders cancer cells susceptible to radiation and chemotherapy. Recently, the concept of “synthetic lethality” has been successfully used to exploit the genomic instability of cancer cells. For example, the DNA repair-defective BRCA1/2-deficient cells are highly sensitive to PARP inhibitors. In this application, I propose a new synthetic lethal strategy to target cancer cells expressing APOBEC3A with inhibitors of the ATR checkpoint kinase. My proposed studies may reveal a key function of ATR in response to APOBEC3A-induced DNA damage. Developing a strategy to specifically kill APOBEC3A-expressing cancer cells will be a breakthrough in targeted cancer therapy. My career goal is to obtain a research faculty position at a leading institute where I will dissect the mechanisms of APOBEC3A-causing genomic instability in cells. However, my successful transition to independence in this field would be significantly bolstered by augmenting my expertise in cell biology techniques with new training opportunities in mouse cancer models. It is with these acquired skills that I will be able to investigate whether ATR inhibitors can be used to specifically target cancer cells expressing APOBEC3A. The success of this project will be greatly enhanced by the outstanding collaborators that I have assembled to advise me throughout my transition to independence. In addition, the exceptional research environment available at MGH and the Harvard Medical School area has all of the necessary resources required for the proposed training and research studies. The K99/R00 award would provide me with the protected time needed for this advanced training and allow me to continue to foster my growth under the mentorship of Dr. Zou. I expect that the protected time provided by this award will allow me to elucidate the function of ATR in cells overexpressing APOCBEC3A and to determine whether ATR inhibitors (ATRi) can be used to promote synthetic lethality in cancer cells with high levels of APOBEC3A. In aim 1, I will elucidate how ATR inhibition leads to cell death in APOBEC3A expressing cells. In aim 2, I will determine what is the target of APOBEC3A in human cells. Finally in aim 3, I will investigate whether ATR inhibitors can be used to specifically target cancer cells expressing APOBEC3A. Despite my recent training in biochemistry and cell biology, I will need 1-2 additional years of training to establish myself as an independent investigator. Receipt of this award would not only allow me to expand my research plan, but also establish myself as a primary investigator in the field of cancer biology