Researchers have uncovered how non–small cell lung cancer (NSCLC) tumors may develop drug resistance over time and identified the APOBEC3A protein as a potential target for novel cancer therapeutics, according to a study published by Isozaki et al in Nature. The findings point to potential solutions for treating tumors that have become resistant to standard cancer therapies.
Background
Cancer therapies that target specific genetic abnormalities in tumors have revolutionized treatment possibilities over the past 20 years. While quality of life and survival have improved with these targeted therapies, patients often experience relapses as a result of the evolution of new tumor cells that are resistant to the agents.
“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 co–senior study author Michael Lawrence, PhD, Assistant Professor of Pathology at Harvard Medical School and an assistant geneticist at the Massachusetts General Hospital 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,” he highlighted.
Study Methods and Results
In the new study, the researchers performed genetic analyses on the NSCLC tumors of patients who were treated with tyrosine kinase inhibitors as well as experimentally derived tyrosine kinase inhibitor–resistant tumor cells. The researchers found that in both settings, the small number of tumor cells that survived treatment with tyrosine kinase inhibitors accumulated mutations of the APOBEC mutational signature and demonstrated overexpression of the APOBEC3A protein.
The researchers provided two lines of reasoning to identify this overexpression as a main driver of drug resistance. They emphasized that APOBEC3A can directly cause mutations that are known to result in tumor resistance, such as mutations in the ALK gene. In other cases, APOBEC3A can cause extensive DNA damage that helps push tumor cells into a persister state, though the cause of drug resistance in this instance is less direct.
The researchers determined that cell lines without the APOBEC3A gene did not become resistant to targeted therapies as fast as those with the gene, suggesting that targeting APOBEC could extend patients’ responses to existing targeted therapies. However, no therapeutics currently exist to target APOBEC.
Conclusions
In future studies, the researchers hope to gain further insight into the mechanisms by which APOBEC causes drug resistance and shed light on how to develop agents inhibiting APOBEC expression or activity. While many patients with NSCLC who have targeted therapy–resistant tumors have APOBEC3A mutations, the patients that do not have these mutations would require other therapies. Further, the researchers noted uncertainties regarding whether APOBEC drives acquired drug resistance in other cancer types or with use of other targeted 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,” explained co–senior study author Aaron Hata, MD, PhD, Assistant Professor of Medicine at Harvard Medical School and an assistant physician in the Department of Hematology and Oncology at the Massachusetts General Hospital 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,” he concluded.
Disclosure: The research in this study was funded by grants from the National Institutes of Health, the Doris Duke Charitable Foundation Clinical Scientist Development Award, Smith Family Foundation Award, Rullo Family Innovation Award, SU2C/NSF/V Foundation Convergence Award, the Ludwig Center at Harvard, Tosteson & FMD Award, Lung Cancer Research Foundation, the Lungstrong Foundation, Targeting a Cure for Lung Cancer, Be a Piece of the Solution, the Landry Family, and the Suzanne E. Coyne Family; and in part by Amgen, Blueprint Medicines, BridgeBio, Bristol-Myers Squibb, C4 Therapeutics, Eli Lilly, Novartis, Nuvalent, Pfizer, Roche/Genentech, Scorpion Therapeutics. For full disclosures of the study authors, visit nature.com.
