Scientists have revealed the inner workings of a key protein involved in colon cancer, paving the way for new drugs to treat the disease.
The tankyrase protein is involved in a wide variety of processes in the cell, meaning it could lead to better and less toxic cancer drugs, researchers suggest.
Using Nobel Prize-winning techniques, scientists discovered how the protein turns itself on and off by self-assembling into 3D chain-like structures.
The elusive but important protein plays an especially important role in helping drive colon cancer.
Scientists at The Institute of Cancer Research, London (ICR), believe their research will open the door to new forms of cancer treatment 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 vital new information about a particular protein molecule called tankyrase, which plays an important role in colon cancer and other diseases, but has so far eluded our understanding. .
“We are playing catch-up – we have all these drugs to prevent tankyrase from being produced, but we don’t have enough basic knowledge to use them as treatments.
“We have shown how tankyrase is switched on and can go from a ‘lazy’ enzyme to an active enzyme.
“If we can make better, less toxic drugs to control this process, we could pave the way for effective colon cancer treatment in the future.”
According to the findings published in Nature, the fundamental discovery could have implications for the treatment of various cancers, as well as diabetes and inflammatory, heart and neurodegenerative diseases.
Professor Kristian Helin, chief executive of the ICR, said: “These fundamental findings help us understand how the all-important tankyrase protein works in cells.
“Almost all colon cancers have hyperactive Wnt signaling acting through tankyrase, and so they could potentially be treated with drugs that target it.
“I am hopeful that these major advances in our understanding of tankyrase will help us overcome the limitations of currently available drug candidates – hopefully moving us one step closer to a new targeted treatment for colon cancer.
“Tankyrase is also responsible for regulating a wide variety of processes relevant to a variety of diseases, not just cancer, so this research could have broad implications.”
Over the past 10 years, scientists have been developing drugs to block tankyrase in an attempt to treat colon cancer — but because of the complexity of the processes it’s involved in, the drugs led to too many side effects to reach clinical trials.
To really understand how tankyrase inhibitors work and how to develop less toxic treatments, ICR scientists set out to uncover new structural information using advanced cryo-electron microscopy.
This extremely powerful type of microscopy freezes samples at -180 °C to visualize the finest details of the protein shape.
This allowed them to visualize and record how tankyrase ‘assembles’ itself into fibers – chain-like structures – and why fiber formation is necessary for tankyrase to activate itself.
Researchers believe specific regions of the protein that allow it to assemble and disassemble into different structures are exciting targets for future cancer drugs.
The hope is that they will be able to design structurally different tankyrase inhibitors – ones that are safer and more effective, which are urgently needed for the treatment of colon cancer and other diseases with which tankyrase has been linked.
The study was funded primarily by Cancer Research UK, Wellcome and the ICR.