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A new study from researchers at the Mass General Cancer Center has uncovered a protein that is implicated in lung cancer resistance to tyrosine kinase inhibitor (TKI) therapies. The research, published Wednesday in Nature suggest the protein, APOBEC3A, could be a promising target for therapeutic development.

“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.”

For this research, the Mass General investigators analyzed tumor cells from non-small cell lung cancer (NSCLC) that had been treated with a class of targeted therapies, TKIs. Using bother patient tumors, as well as experimentally derived TKI-resistant cancer cells, genetic analysis revealed that in both sets of samples, tumor cells that survived TKI therapy accumulated mutation of the APOBEC mutation signature. The surviving cells expressed APOBEC3A, which they determined drove therapy resistance in two ways.

First, APOBEC3A was directly responsible for driving mutations that are known to cause tumor resistance, such as the ALK gene. In the second instance, the researcher said APOBEC3A’s contribution to resistance is not as direct, but the team hypothesized that the protein causes damage to DNA that influences the tumor cells into a “persister” state, making them more resistant to treatment.

Following these discoveries, the Mass General researchers showed that cell lines with the APOBEC3A gene knocked out did not develop therapy resistance as those cells that contained the gene, suggesting targeting it could help lengthen the time a patient is responds to TKIs or 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.”

Building on these new findings, the team will look to develop a better understanding of the mechanisms at play that allow APOBEC to influence lung cancer resistance to TKIs, information they said could help influence potential therapeutic development. Further research could also uncover whether APOBEC is responsible for drug resistance in other tumor types, or if it also influences resistance when other targeted therapies are used.

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