Researchers discovered how to turn on cancer’s ‘kill switch’

Cells have a natural editing system that allows them to rearrange genetic instructions to create different proteins from the same gene. This process, called alternative RNA splicing, fine-tunes how proteins function, enabling cells to respond to different needs. But in cancer, this process often goes haywire, helping tumors grow and resist treatment.

Scientists have long known that abnormal RNA splicing plays a role in cancer. Many tumors show disrupted patterns of splicing, driven by mutations or imbalances in splicing regulators—proteins that determine which parts of a gene get included or skipped.

One of these key regulators, TRA2β, is frequently overactive in aggressive cancers, including breast, brain, and colorectal tumors. Until recently, no therapies targeted TRA2β directly. But now, researchers have discovered a way to shut it down using a molecular switch hidden within its own RNA.

In healthy cells, TRA2β levels are controlled by a built-in safety mechanism known as a poison exon. This small genetic sequence can insert itself into the TRA2β RNA message, marking it for destruction before it can be turned into protein. Think of it as a self-destruct button that prevents excessive TRA2β activity.

However, in cancer, this poison exon is frequently skipped, allowing TRA2β levels to rise unchecked. High levels of this protein fuel tumor growth by influencing the splicing of other key genes involved in cell division, DNA repair, and programmed cell death. Scientists have found that tumors with low poison exon activity tend to be more aggressive and are linked to poorer survival rates in patients.

“We’ve shown for the first time that low levels of poison exon inclusion in the TRA2β gene are associated with poor outcomes in many different cancer types, and especially in aggressive and difficult-to-treat cancers,” said Olga Anczuków, an associate professor at The Jackson Laboratory (JAX) and co-program leader at the NCI-designated JAX Cancer Center. These include breast cancer, brain tumors, ovarian cancers, skin cancers, leukemias, and colorectal cancers, she explained.

To counteract this cancerous activity, researchers at JAX and UConn Health developed a strategy to reactivate TRA2β’s poison exon using antisense oligonucleotides (ASOs). These synthetic RNA fragments are designed to bind precisely to the TRA2β RNA, forcing the poison exon back into the sequence.

When introduced into cancer cells, ASOs restored the natural self-destruct mechanism. “We found that ASOs can rapidly boost poison exon inclusion, essentially tricking the cancer cell into turning off its own growth signals,” said Nathan Leclair, an MD/PhD graduate student who led the study.

This method proved effective across multiple cancer types. ASOs targeting the poison exon significantly reduced tumor cell survival in lab-grown cancer models, including breast, lung, and brain cancer. Unlike chemotherapy, which often harms healthy cells, ASOs appeared highly specific to cancerous cells. “These poison exons work like a rheostat, quickly adjusting protein levels—and that could make ASOs a highly precise and effective therapy for aggressive cancers,” Leclair added.

One of the most surprising findings in the study was that eliminating TRA2β protein entirely did not stop tumor growth. When researchers used CRISPR gene editing to completely remove TRA2β, tumors continued to thrive. This suggested that simply reducing the protein may not be enough to halt cancer. Instead, the poison exon itself seems to play a larger role.

“This tells us that poison-exon-containing RNA doesn’t just silence TRA2β,” explained Anczuków. “It likely sequesters other RNA-binding proteins, creating an even more toxic environment for cancer cells.” In other words, the poison exon’s impact extends beyond TRA2β, disrupting multiple pathways that tumors rely on for survival.

The researchers further tested the approach in three-dimensional organoid models—tiny, lab-grown tumors that mimic real cancer—and in mouse models of human cancer. In both cases, targeting the poison exon led to reduced tumor growth, strengthening the case for ASO-based therapies.

This research opens the door to a new class of cancer treatments focused on restoring natural RNA regulatory mechanisms rather than blocking proteins directly. Because ASOs can be designed to target specific splicing errors, they may offer a more refined alternative to traditional drugs, potentially reducing side effects and improving effectiveness.

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 function, making them promising candidates for future cancer treatments.

This research was supported by the National Institutes of Health and the NCI-designated JAX Cancer Center.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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