APOBEC3A

A research team has discovered the key role that the APOBEC3A and APOBEC3B enzymes play in driving cancer mutations by modifying the DNA in tumor genomes, offering potential new targets for intervention strategies. A research team led by the University of California, Irvine has discovered the key role that the APOBEC3A and APOBEC3B enzymes play in driving cancer mutations by modifying the DNA in tumor genomes, offering potential new targets for intervention strategies. The study, published today online in the journal Nature Communications, describes how the researchers identified the process by which APOBEC3A and APOBEC3B detect specific DNA structures, resulting in mutations at distinct positions within the tumor genome. "It's critical to understand how cancer cells accumulate mutations leading to hot spots that contribute to disease progression, drug resistance and metastasis," said corresponding author Rémi Buisson, UCI assistant professor of biological chemistry. "Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumors, but until now we did not know how to identify the specific type caused by each. This finding will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly." In this study, graduate student Ambrocio Sanchez and postdoctoral fellow Pedro Ortega, both in Buisson's laboratory at the UCI School of Medicine, developed a new method to characterize the particular kind of DNA modified by APOBEC3A and APOBEC3B. It revealed that the two enzymes do not recognize the same DNA sequences and structures within the genomes of cancer cells. Based on this observation, an innovative approach utilizing these unique target preferences was employed to classify cancer patients who had accumulated mutations caused by each enzyme. "The next steps are to investigate whether mutations caused by these enzymes lead to various types of therapy resistance. It's also critical to identify molecules that inhibit APOBEC3A and APOBEC3B to prevent mutations from forming. Our findings could, in the future, help to assess patient risk before treatment and suppress tumor evolution using the appropriate drug therapy," Buisson said. Other team members included undergraduate and graduate students and postdoctoral fellows from UCI, Harvard Medical School, the University of Southern California, the University of Texas at San Antonio and the University of Minnesota. This work was supported by the National Institutes of Health's Research Supplements to Promote Diversity in Health-Related Research program under award R37-CA252081-S; California Institute for Regenerative Medicine stem cell biology training grant TG2-01152; European Molecular Biology Organization postdoctoral fellowship ALTF 213-2023; Cancer Prevention and Research Institute of Texas research training award RP 170345 and Recruitment of Established Investigators award CPRIT RR220053; the National Cancer Institute under awards R37-VA252081 and P01-CA234228; the National Institute of Allergy and Infectious Diseases under award R01 AI150524; and access to UCI's Genomics Research and Technology Hub, affiliated with the Chao Family Comprehensive Cancer Center, under grant P30-CA062203.

过去二十年来，针对肿瘤中特定基因异常的癌症疗法彻底改变了治疗的可能性。虽然靶向治疗提高了生活质量和生存率，但由于对靶向治疗产生抗药性的新肿瘤细胞的进化，复发很常见。 过去二十年来，针对肿瘤中特定基因异常的癌症疗法彻底改变了治疗的可能性。虽然靶向治疗提高了生活质量和生存率，但由于对靶向治疗产生抗药性的新肿瘤细胞的进化，复发很常见。 在一项新的研究中，来自美国麻省总医院癌症中心等研究机构的研究人员揭示了肺部肿瘤如何随着时间的推移产生耐药性，并指出一种名为APOBEC3A的蛋白可能是一种有希望的靶标。这一发现可能有助于科学家们开发新的解决方案，解决肿瘤对癌症靶向疗法的耐药性问题。相关研究结果于2023年7月5日在线发表在Nature期刊上，论文标题为“Therapy-induced APOBEC3A drives evolution of persistent cancer cells”。 论文共同通讯作者、麻省总医院癌症中心医学博士Aaron Hata说，“传统上，我们用一种药物治疗病人，直到肿瘤进展，然后我们看看肿瘤中发生了什么，并试图根据我们在肿瘤中看到的情况决定下一种疗法。从这个意义上说，肿瘤总是领先一步，我们需要对它做出反应。通过了解肿瘤进化的基本机制，我们可以领先肿瘤一步，了解是什么在驱动它，并能更早地进行干预。” 在这项新的研究中，这些作者分析了接受酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）治疗的非小细胞肺癌（NSCLC）肿瘤细胞，其中TKI是一种靶向疗法。他们对患者肿瘤以及实验衍生的TKI耐药性肿瘤细胞进行了基因分析，发现在这两种情况下，TKI治疗后存活下来的一小部分肿瘤细胞都积累了APOBEC突变标记（mutation signature）的突变。 这些作者发现，TKI治疗后存活的肿瘤细胞过表达一种APOBEC蛋白：APOBEC3A，它似乎通过两种主要方式导致耐药性。APOBEC3A可直接导致已知会导致肿瘤耐药的突变，如ALK基因突变。在其它情况下，耐药性的原因并不那么直接，但是他们假设APOBEC3A会造成广泛的DNA损伤，这有助于将肿瘤细胞推向更耐药的“持久性”状态。 这些作者证实，不含APOBEC3A基因的肿瘤细胞系对靶向疗法产生耐药性的速度不如含有该基因的肿瘤细胞系快。这表明靶向APOBEC可能会延长患者对现有靶向疗法的反应；然而，目前还没有靶向APOBEC的药物。 图片来自Nature, 2023, doi:10.1038/s41586-023-06303-1。 展望未来，这些作者希望进一步深入了解APOBEC导致耐药的机制，从而可能为如何开发抑制APOBEC表达或活性的药物提供更多启示。虽然许多对靶向疗法产生耐药性的NSCLC患者都有APOBEC突变，但没有这些突变的患者则需要其他解决方案。此外，目前还不清楚APOBEC是否会导致其他癌症类型或对其他靶向疗法产生获得性耐药性。 论文共同通讯作者、麻省总医院癌症中心的Michael Lawrence博士说，“在基因组时代开发的许多新的癌症疗法都是专门针对‘驱动突变’的，因此它们不会伤害健康细胞，只会影响具有驱动肿瘤进展的突变的肿瘤细胞。然而，肿瘤往往会复发，因为它已经发生了变化，能够在靶向药物作用下存活。我们的研究有助于我们了解驱动耐药过程的机制，这类机制在肿瘤产生耐药性之前就已经开始了。”（生物谷 Bioon.com） 参考资料： Hideko Isozaki et al. Therapy-induced APOBEC3A drives evolution of persistent cancer cells. Nature, 2023, doi:10.1038/s41586-023-06303-1.

Cancer therapies that target specific genetic abnormalities in tumors have revolutionized treatment possibilities over the past two decades. While quality of life and survival are improved with targeted therapies, relapse is common due to the evolution of new tumor cells that are resistant to the targeted therapy. A new study reveals how lung tumors may develop drug resistance over time, pointing to a protein, called APOBEC3A, that could be a promising target. Results may help researchers develop new solutions for tumor resistance to targeted cancer therapies. Cancer therapies that target specific genetic abnormalities in tumors have revolutionized treatment possibilities over the past two decades. While quality of life and survival are improved with targeted therapies, relapse is common due to the evolution of new tumor cells that are resistant to the targeted therapy. A new study by investigators from the Mass General Cancer Center, a member of the Mass General Brigham healthcare system, reveals how lung tumors may develop drug resistance over time, pointing to a protein, called APOBEC3A, that could be a promising target. Results, published in Nature, may help researchers develop new solutions for tumor resistance to targeted cancer therapies. "Traditionally, we treat patients with a drug until the tumor progresses and then we look at what happened in the tumor and try to decide on the next therapy based on what we see in the tumor," said corresponding author Aaron Hata, MD, PhD, of the Mass General Cancer Center. "In that sense, the tumor is always one step ahead and we need to react to it. By understanding the fundamental mechanisms of tumor evolution, we can get ahead of the tumor, understand what's driving it, and be able to intervene earlier." In this study, the authors analyzed non-small-cell lung cancer (NSCLC) tumor cells treated with tyrosine kinase inhibitors (TKIs), a type of targeted therapy. The researchers performed genetic analysis on patient tumors as well as experimentally derived TKI-resistant cells, finding that in both settings, the small population of tumor cells that survived after TKI treatment accumulated mutations of the APOBEC mutation signature. The authors found that the tumor cells surviving TKI treatment overexpress a type of APOBEC protein, APOBEC3A, which appears to cause drug resistance in two main ways. APOBEC3A can directly cause mutations that are known to result in tumor resistance, such as mutations in the ALK gene. In other cases, the cause of drug resistance is less direct, though the researchers hypothesize that APOBEC3A causes extensive DNA damage that helps push tumor cells into a "persister" state that is more resistant to treatment. The researchers demonstrated that cell lines without the APOBEC3A gene did not become resistant to targeted therapies as fast as those with the gene. This suggests that targeting APOBEC could extend patients' response to existing targeted therapies; however, no drug exists yet to target APOBEC. Going forward, the researchers hope to gain further insight into the mechanisms by which APOBEC causes drug resistance, which may shed more light on how to develop a drug to inhibit APOBEC expression or activity. While many NSCLC patients with targeted therapy-resistant tumors have APOBEC mutations, the patients that do not have these mutations would require other solutions. Furthermore, it is not yet clear whether APOBEC drives acquired drug resistance in other cancer types or with use of other targeted therapies. "Many new cancer therapies that have been developed in the genomic era specifically target 'driver mutations,' such that they do not hurt healthy cells and only affect cells with the mutation driving the tumor progression," said corresponding author Michael Lawrence, PhD, of the Mass General Cancer Center. "Very often, however, a tumor will return, having undergone a change that allows it to survive in the presence of the drug. Our research helps us understand the mechanisms that drive the process of drug resistance, which begin before the tumor becomes resistant."