CNIO researchers solve 30-year mystery of oncogenic protein that "refuels" on cellular waste to drive lung and thyroid cancers

Spanish researchers discover CCDC6-RET protein uses both ATP and ADP to self-activate, explaining its role in rapid tumor growth and therapy resistance.

By: AXL Media

Published: Apr 30, 2026, 9:24 AM EDT

Source: Information for this report was sourced from EurekAlert!

A Paradigm Shift in Cancer Metabolism

The CCDC6-RET protein, a known driver of thyroid and lung cancers, has eluded structural explanation since its discovery over three decades ago. However, new research from the National Cancer Research Centre (CNIO) in Spain has finally mapped the architecture of this oncogenic "chimera." Published in Nature Communications, the study reveals that CCDC6-RET manages to self-activate—effectively giving itself the order to begin cellular division—without the need for external protein interference. This finding explains why the activation of this fusion protein is significantly faster than its non-fused counterparts, creating a rapid-fire environment for tumor growth.

The "Dual-Fuel" Discovery: ATP and ADP

The most startling revelation from the CNIO team involves the protein's energy source. Typically, protein kinases use ATP (adenosine triphosphate) as fuel, leaving behind ADP (adenosine diphosphate) as a waste product once a phosphate group is consumed. The study found that CCDC6-RET is the first known kinase capable of utilizing both ATP and its "exhaust fumes," ADP, to power its activation. Lead author Iván Plaza notes that this ability allows the protein to re-energize itself even when ATP is scarce, a common condition in the high-demand environment of a growing tumor. This discovery suggests that ADP is not merely a byproduct but an active signaling molecule in cancer metabolism.

Architecture of a Genetic Fusion

The CCDC6-RET protein is created when the RET gene, which is normally responsible for healthy cell division, abnormally fuses with another gene. These genetic fusions often create proteins that are far more aggressive than their original forms. By combining advanced structural biology techniques with artificial intelligence, the CNIO group reconstructed a three-dimensional model of the protein in both its active and inactive states. This visualization allowed researchers to see exactly how the "chimera" structure facilitates simultaneous activation of all its components, rather than the progressive, step-by-step activation seen in healthy RET proteins.