When mutated and overexpressed, MYC is a gene that drives tumor growth in multiple cancer types. Researchers have been on a mission to target this important gene but effectively achieving this goal has been a challenge. Now a University of Pennsylvania-led research team has identified a pathway that serves as a partner to MYC and ultimately may be its “Achilles’ Heel.” This pathway involves a protein called ATF4 and the research team utilizing cell lines and mouse models have found that ATF4 is blocked it can cause cancer cells to produce too much protein and essentially self-destruct. We may be upon a new therapeutic approach focusing on inhibitors that block synthesis of ATF4 exist today.
What follows is a brief Question and Answer format to break down the recent study and associated MedicalXpress article.
What is MYC?
A gene that controls normal cell growth, however when mutated or amplified in cancer it triggers a chain reaction that supports out of control tumor growth.
Is there any specific way to target it?
Are there other ways around this?
Possibly. Some previous research has evidenced the blocking of other steps in the chain as a workaround to slow cancer growth. For example, the University of Pennsylvania research group has revealed that in previous research certain tumors one of the steps is regulated by a kinase called PERK which activates ATF4.
Blocking PERK Work?
Blocking PERK doesn’t always stop tumor growth due to the fact that MYC actually controls a second process that can run in parallel as a sort of redundancy in the system. This second kinase is called GCN2.
What have they Learned thus far at the University of Pennsylvania?
One of their lead investigators notes “What we’ve learned is that we need to go further downstream to block tumor growth in a way that cancer cells cannot easily escape” and the group think s they have identified the target to accomplish this.
An alternative approach nicely summarized in MedicalXpress is to target ATF4 as it is the point where both signal pathways converge. This means that there less redundancy built in to allow cancer to survive. Their study findings evidence that ATF4 turns on the genes MYC needs for growth and controls the rate at which cells make specific proteins called 4E-BP.
The team blocked out ATF4 in cell lines and mice and found tumor cells continued to build up proteins and eventually died due to stress. This acted to actually block tumor growth in the mice with lymphomas and colorectal cancer!
Additionally, the team found that tumors in humans driven by MYC, ATF4 and its protein partner called 4E-BP are overexpressed—evidencing that the findings here may point to an approach that could actually work in humans.
Constantinos Koumenis, the co-senior author noted, “What we’ve learned is that we need to go further downstream to block tumor growth in a way that cancer cells can’t easily escape, and our study identifies the target to do just that.” Feven Tamiere, Ph.D., was involved while a doctoral candidate, “This shows us the potential impacts of targeting ATF4 in MYC-dependent tumors, something we’re already studying. We’re also working to confirm this approach will not cause any serious off-target effects.”
Constantinos Koumenis, Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania
David Ruggero, School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco