Targeting APOBEC3A-expressing cancer cells with ATR inhibitors

项目摘要 基因组不稳定是癌症的标志。一方面，癌细胞的基因组不稳定性促进了 肿瘤抑制因子的丢失和癌基因的激活。另一方面，基因组的不稳定性使癌症 对放疗和化疗敏感的细胞。最近，“合成杀伤力”的概念被 成功地利用了癌细胞基因组的不稳定性。例如，DNA修复缺陷 BRCA 1/2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 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 提出的研究可能揭示ATR在响应APOBEC3A诱导的DNA损伤中的关键功能。 开发特异性杀死表达APOBEC3A的癌细胞的策略将是靶向治疗的突破。 癌症治疗 我的职业目标是在一家领先的研究所获得一个研究员的职位，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 如果我在细胞生物学方面的专业知识得到加强，我在这一领域的独立性将得到极大的加强 在小鼠癌症模型中提供新的训练机会。有了这些技能， 能够研究ATR抑制剂是否可以用于特异性靶向表达 APOBEC3A。这个项目的成功将大大提高了优秀的合作者，我有 在我向独立过渡的过程中给我提供建议此外，特殊的研究 在MGH和哈佛医学院地区提供的环境拥有所有必要的资源 建议的培训和研究所需的。K99/R00奖将为我提供 保护时间需要这种先进的培训，让我继续促进我的成长下， 邹博士的指导。我希望这个奖项所提供的受保护的时间将允许我阐明 ATR在过表达APOCBEC 3A的细胞中的功能，并确定ATR抑制剂（ATRi）是否可以被 用于促进具有高水平APOBEC3A的癌细胞的合成致死性。在目标1中，我将阐明如何 ATR抑制导致表达APOBEC3A的细胞中的细胞死亡。在目标2中，我将确定什么是目标 人细胞中的APOBEC3A。最后，在目标3中，我将研究ATR抑制剂是否可以用于 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年的培训， 让自己成为一名独立调查员获得这个奖项不仅可以让我扩大我的 研究计划，但也确立了自己作为一个主要研究人员在癌症生物学领域

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