Researchers in Spain have identified a protein linked to cancer that can activate itself at unusual speed, potentially reshaping how scientists approach certain tumors. The discovery centers on a fusion protein known as CCDC6-RET, which plays a role in thyroid cancer and lung adenocarcinoma.
Scientists at the National Cancer Research Centre (CNIO) found that this protein bypasses typical activation steps. Instead, it triggers its own activity without relying on other cellular signals. Additionally, the process unfolds faster than what researchers see in normal proteins.
The finding challenges long-standing assumptions about how RET-related cancers develop. Researchers have studied RET fusions for decades, yet key details about their behavior remained unclear. However, this new work begins to fill in those gaps.
In healthy cells, proteins like RET activate gradually. They add phosphate groups step by step using energy from ATP molecules. Consequently, this controlled process helps regulate cell growth and division.
The CCDC6-RET fusion behaves differently. It activates all its components at once rather than in sequence. Furthermore, it accelerates this process in a way that may drive tumor growth more aggressively.
Researchers also discovered a second, unexpected mechanism. After using ATP, the protein can draw energy from ADP, a molecule long considered waste. In addition, this ability allows the protein to recycle energy instead of discarding it.
Scientists compared the effect to refueling a car using exhaust fumes. The analogy illustrates how unusual the mechanism appears in biological systems. However, the implications could prove significant for cancer treatment.
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Dual mechanism may explain why some therapies fail
The research team noted that some kinases can use ADP. Yet this marks the first known case of a kinase using both ATP and ADP efficiently. Consequently, the protein gains greater flexibility in how it operates.
This flexibility may help cancer cells survive under stress. Tumors often face limited nutrients or targeted drug treatments. Meanwhile, the ability to draw from multiple energy sources may give them an edge.
Researchers believe this dual mechanism could explain why some therapies fail. Current treatments target RET fusions but may not account for this added complexity. Therefore, drugs might miss part of the activation process.
The team emphasized the need to study this mechanism in detail. They argue that understanding how the protein self-activates could guide better drug design. Additionally, it may help researchers develop therapies that block both energy pathways.
The study also produced a detailed three-dimensional model of the protein. Scientists used structural biology techniques alongside artificial intelligence tools. Furthermore, they mapped both inactive and active states of CCDC6-RET.
These models show how the protein changes shape during activation. They also reveal how its structure supports rapid and simultaneous activation. Consequently, researchers now have a clearer view of its inner workings.
The work could extend beyond a single protein. Scientists have identified roughly 20 RET fusion variants in different cancers. In addition, the same approach may help analyze those related proteins.
The research team sees broader implications for cancer biology. Fusion genes often create “chimeric” proteins that behave differently from normal ones. However, scientists still struggle to predict their effects.
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Shift could open new research options
CCDC6-RET offers a clearer example of how these fusions operate. It demonstrates how combining two genes can produce entirely new behaviors. Furthermore, it shows how those behaviors can drive disease progression.
The findings may also shift how scientists view cellular energy systems. ADP has long been considered a byproduct of energy use. Meanwhile, this study suggests it can play an active role in signaling.
That shift could open new research directions. Scientists may now examine whether other proteins use similar mechanisms. Additionally, it may lead to broader insights into tumor metabolism.
The study’s authors stress that this discovery does not immediately change treatment. However, it provides a stronger foundation for future therapies. Consequently, researchers can begin designing drugs with this mechanism in mind.
They also note that cancer cells often adapt quickly. Targeting one pathway may not be enough if others remain active. Therefore, therapies may need to block multiple activation routes simultaneously.
The discovery arrives after decades of research into RET fusions. Despite that long history, many details remained unresolved until now. Furthermore, this work shows how new tools can reveal hidden mechanisms.
By combining structural analysis with modern computational methods, researchers gained a deeper understanding. Additionally, they created a model that others can build upon.
The study adds momentum to efforts to better understand cancer at the molecular level. Scientists continue to uncover how small changes in proteins can have large effects. Meanwhile, each discovery brings new opportunities to refine treatment strategies.
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