Scientists have revealed the inner workings of a key protein involved in colorectal cancer, paving the way for new drugs to treat the disease.
The tankyrase protein is involved in many cell processes, which means it could lead to better and less toxic cancer drugs, the researchers suggest.
Using Nobel Prize-winning techniques, scientists have discovered how a protein turns itself on and off by self-assembling itself into 3D-chain-like structures.
This elusive but important protein plays a particularly important role in supporting colorectal cancer.
Researchers at The Institute of Cancer Research in London (ICR) believe their research will open the door to new types of cancer treatments that can control tankyrase more precisely than is currently possible with fewer side effects.
Study leader Professor Sebastian Guettler, Deputy Head of the Department of Structural Biology at the ICR, said: “Our study has provided important new insights into a specific protein molecule called tankyrase, which plays an important role in colorectal cancer and other diseases, but has so far eluded our understanding. understanding.
“We’re playing catch-up – we have all these drugs that block the formation of tankyrase, but we don’t have enough basic knowledge to use them as a treatment.
“We have shown how tankyrase is activated and can go from a ‘lazy’ to an active enzyme.
“If we can create better, less toxic drugs to control this process, we could pave the way for successful treatment of colorectal cancer in the future.”
According to the findings published in Nature, the fundamental discovery could have implications for the treatment of a variety of cancers, as well as diabetes, inflammatory, heart and neurodegenerative diseases.
Professor Kristian Helin, Chief Executive of the ICR, said: “These fundamental discoveries help us understand how the all-important tankyrase protein works in cells.
“Almost all colorectal cancers have hyperactive Wnt signaling, which acts via tankyrase, and thus could potentially be treated with drugs that target it.
“I hope these key advances in our understanding of tankyrase will help us overcome the limitations of currently available drug candidates – hopefully bring us one step closer to a new targeted treatment for colorectal cancer.
“Tankyrase is also responsible for regulating a wide range of processes related to various diseases, not just cancer, so this research could have broad implications.”
Over the past 10 years, scientists have developed drugs that block tankyrase to treat colorectal cancer – but due to the complexity of the processes it is involved in, these drugs have led to too many side effects to pass clinical trials.
To truly understand how tankyrase inhibitors work and how to develop less toxic treatments, ICR scientists set out to uncover new structural information using state-of-the-art cryo-electron microscopy.
This extremely powerful type of microscopy freezes samples at -180°C to allow imaging of the finest details of protein shape.
This allowed them to visualize and capture how tankyrase “self-assembles” into filaments – chain-like structures – and why filament formation is needed for tankyrase self-activation.
Scientists believe that the specific regions of the protein that allow it to assemble and disassemble into different structures are exciting targets for future anti-cancer drugs.
The hope is that they will be able to design structurally different tankyrase inhibitors – safer and more effective, which are urgently needed to treat colorectal cancer and other diseases that tankyrase has been associated with.
The study was funded primarily by Cancer Research UK, Wellcome and ICR.