LMP researchers discover effective molecular switch for most notorious cancer-causing gene

Monday, October 27, 2014
Severa Bunda and Michael Ohh
Severa Bunda and Michael Ohh

By Katie Babcock and Michelle Lee

For over thirty years, scientists and pharmaceutical companies have struggled to target one of the most well-known cancer-causing proteins. Mutations in this oncoprotein are responsible for over 30 percent of all cancers, and if you include the pathways they govern, they could be involved in virtually all cancers. In a remarkable breakthrough, researchers from the University of Toronto have discovered a missing link that could target this oncoprotein and provide more effective treatment.

Professor Michael Ohh (PhD), of the Department of Laboratory Medicine and Pathobiology (LMP) and Postdoctoral Fellow Severa Bunda, recently published their findings in the Proceedings of the National Academy of Sciences of the United States of America.

In this study, they have revealed a critical process that inactivates the Ras oncoprotein. The Ras oncoprotein is like a switch. When it’s involved in normal cell proliferation, it switches on and off in a well-regulated manner. But when it mutates, its switch is permanently turned ‘on’ leading to uncontrollable cell growth and cancer.

“We found that there is a critical modification on Ras that has not been identified before,” said Prof. Ohh. “This Ras protein has been around for decades and is involved in many cancers including prostate, breast, pancreas, and brain cancer. The significance of this modification is that it seems to govern the Ras oncoprotein’s major function as an on/off switch for cancer.”

They discovered that Ras is switched off by another oncoprotein called Src. Scientists previously knew that the two were connected and had been trying to inactivate one or the other. However, Ras is difficult to target and inactivating Src is not necessarily beneficial because it can make cancers more aggressive in certain settings.

“People always thought that we should turn both genes off, but if you turn Src off, you allow Ras to become even more aggressive,” remarked Bunda. “The idea is not to turn the switch off completely but to balance it.”

Instead of completely turning these oncogenes off, Prof. Ohh and Bunda have discovered that Src can also act as a dimmer switch. With this knowledge, they can stop the growth of cancerous cells.

Scientists had thought that they already knew everything about these oncoproteins that were the first to be discovered.

“This discovery really shows that we need to take a fresh look at old ideas,” said Prof. Ohh. “We asked some of the most basic questions – questions that everyone thought had been answered. But this research shows that when you reexamine the basic science, there is an opportunity to discover things that could have a major impact on treating thousands of patients.”

The team is now testing inhibitors in glioblastoma, one of the most aggressive brain tumours. Their hope is that these inhibitors can be combined with chemotherapy to provide more effective treatment.