New pathway to make cancer self-destruct

Monday, 08 July, 2019

New pathway to make cancer self-destruct

For years, scientists have been trying to target a gene called MYC that is known to drive tumour growth in multiple cancer types when it is mutated or over-expressed, but hitting that target successfully has proven difficult. Now US researchers have identified a new pathway that works as a partner to MYC and may be its Achilles heel.

MYC is a gene that controls normal cell growth, but when it is mutated or amplified in cancer, it sets off a chain reaction that helps tumours grow uncontrollably. While there is currently no specific way to target it, previous research has focused on blocking other steps in the chain as a workaround to impede tumour growth.

Researchers from the University of Pennsylvania, led by Constantinos Koumenis, have previously shown that in certain tumours, one of these steps is regulated by a kinase called PERK, which activates a protein called ATF4. But in their new study, published in Nature Cell Biology, they’ve shown that blocking PERK does not always stop tumour growth because MYC actually controls a second process that can work in parallel as a redundancy in the system. This second kinase is called GCN2, the researchers revealed.

“What we’ve learned is that we need to go further downstream to block tumour growth in a way that cancer cells can’t easily escape, and our study identifies the target to do just that,” Koumenis said.

This study shows the alternative approach is to target ATF4 itself, since it’s the point where both signal pathways converge — meaning there’s less redundancy built in to allow cancer to survive. The findings also show that ATF4 turns on the genes MYC needs for growth and also controls the rate at which cells make specific proteins called 4E-BP.

When the researchers knocked out ATF4 in cells or mice, they found tumour cells continued to build up those proteins and eventually died as a result of stress. This blocked tumour growth in mice with lymphomas and colorectal cancer. This study also found that when tumours in humans are driven by MYC, ATF4 and its protein partner 4E-BP are also overly expressed, which is further evidence that these findings may point to an approach that could work for humans.

These findings in cell lines and mouse models could point the way toward a new therapeutic approach, as inhibitors that can block synthesis of ATF4 already exist. As noted by lead author Feven Tameire, “This shows us the potential impacts of targeting ATF4 in MYC-dependent tumours — something we’re already studying.

“We’re also working to confirm this approach will not cause any serious off-target effects.”

Future studies will also focus on continuing to investigate why ATF4 works the way it does, which may help their understanding of whether there are other potential targets in the chain.

Image credit: ©

Please follow us and share on Twitter and Facebook. You can also subscribe for FREE to our weekly newsletters and bimonthly magazine.

Related News

Human stem cells help treat chronic pain in mice

The team used human induced pluripotent stem cells (iPSCs) derived from bone marrow to make...

Promising drug compounds target liver cancer

Singaporean scientists have discovered four potential drug compounds that target hepatocellular...

Blood pressure drug could help treat alcoholism

A drug used to treat high blood pressure may alleviate anxiety induced by long-term heavy alcohol...

  • All content Copyright © 2020 Westwick-Farrow Pty Ltd