Using Antisense Oligonucleotides to Increase The Level of Toxic Exons in The TRA2β Gene Can Activate The Kill Switch of Cancer Cells

In a new study, researchers from the Jackson Laboratory and UConn Health not only show how cancer hijacks this tightly regulated RNA splicing and rearrangement, but also propose a potential therapeutic strategy to slow down or even shrink aggressive and hard-to-treat tumors. The discovery could change the way people treat aggressive cancers, such as triple-negative breast cancer and certain brain tumors, for which current treatment options are limited.

At the heart of the new research are tiny genetic elements called poison exons, nature's own "switches" for protein production. When these exons are included in RNA messages, they trigger their destruction before proteins are made, preventing harmful cellular activity. In healthy cells, poison exons regulate the levels of key proteins and control genetic machinery. But in cancer, this safety mechanism often fails.

In addition, the researchers found a correlation between the levels of poison exons and patient outcomes. "We have shown for the first time that low levels of toxic exons in the TRA2β gene are associated with poor outcomes in many different cancer types, especially in aggressive and hard-to-treat cancers," said Olga Anczuków, associate professor at the Jackson Laboratory. These cancers include breast cancer, brain tumors, ovarian cancer, skin cancer, leukemia, and colorectal cancer.

Next, they went on to see if they could increase the amount of toxic exons in the TRA2β gene and reactivate this kill switch. They found the answer in antisense oligonucleotides (ASOs), synthetic RNA fragments that can be designed to increase the levels of toxic exons in the TRA2β gene in a specific way. When introduced into cancer cells, the ASOs effectively flipped this kill switch, restoring the body's natural ability to degrade excess TRA2β RNA and inhibit tumor progression.

Figure 1. TRA2β-PE targeting ASO induces anti-cancer phenotypes across tumor cell lines.

"We found that ASOs can rapidly increase levels of toxic exons in the TRA2β gene, essentially inducing cancer cells to turn off their own growth signals," said Nathan K. Leclair, first author of the paper. "These toxic exons work like rheostats, rapidly adjusting protein levels, which could make ASOs a highly precise and effective treatment for aggressive cancers."

Interestingly, when the researchers used CRISPR gene editing to completely remove the TRA2β protein, tumors continued to grow - suggesting that targeting RNA rather than protein may be a more effective approach. "This tells us that poisoning with RNA containing toxic exons does not only silence TRA2β," Anczuków explained. "It may sequester other RNA-binding proteins, creating a more toxic environment for cancer cells."

Further studies will refine ASO-based therapies and explore their delivery to tumors. However, preliminary data suggest that ASOs are highly specific and do not interfere with normal cellular functions, making them promising candidates for future cancer treatments.