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.

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."