Researchers of the Perelman School of Medicine from the University of Pennsylvania (United States) have identified a new way to address cancer treatment that causes tumors to be eliminated due to stress.
For years, researchers have been trying to attack a gene called MYC that is known to boost tumor growth in multiple cancers when mutated or overexpressed, but it has been difficult to achieve that goal successfully. Now, researchers at the University of Pennsylvania have identified a new path that works as a partner of MYC and may be their Achilles heel.
A protein called ATF4 is involved in the new pathway, and when blocked, can cause cancer cells to produce too much protein and die. These findings in cell lines and mouse models, which publishes 'Nature Cell Biology', could point the way to a new therapeutic approach, since there are already inhibitors that can block the synthesis of ATF4.
MYC is a gene that controls the normal growth of cells, but when mutated or amplified in cancer, it triggers a chain reaction that helps tumors grow out of control. While there is currently no specific way to address it, previous research has focused on blocking other steps in the chain as a solution to prevent tumor growth.
The team, led by Constantinos Koumenis, professor Richard Chamberlain of Radiation Oncology and vice president and director of the Radiation Oncology research division, has previously shown that in certain tumors, one of these steps is regulated by a kinase called PERK, which is activated ATF4.
However, this new study has shown that blocking PERK does not always stop tumor growth because MYC actually controls a second process that can work in parallel as a redundancy in the system.
“What we have learned is that we must go lower to block tumor growth in a way that cancer cells can not easily escape, and our study identifies the goal to do just that,” explains Koumenis, lead author of this study together. with Davide Ruggero, professor of Urology at the Helen Diller Comprehensive Family Cancer Center at the University of California, San Francisco (UCSF).
This study shows that the alternative approach is to point to ATF4 itself, since it is the point where both signal pathways converge, which means that there is less built-in redundancy to allow cancer to survive.
The findings also show that ATF4 activates the genes MYC needs for growth and also controls the rate at which cells produce specific proteins called 4E-BP. When the researchers removed the ATF4 in cells or mice, they found that the tumor cells continued to accumulate those proteins and eventually died as a result of stress. This blocked tumor growth in experimental models with lymphomas and colorectal cancer.
This study also found that when tumors in humans are controlled by MYC, ATF4 and its associated protein 4E-BP are also expressed in excess, which is further evidence that these findings may point to an approach that could work for humans .
“This shows us the potential impacts of targeting ATF4 in MYC-dependent tumors, something we are already studying. We are also working to confirm that this approach will not have any effect outside the target, “says researcher Feven Tameire.
The authors believe that future studies will also focus on continuing to investigate why ATF4 works the way it does, which can help to understand if there are other potential targets in the chain.