Transcription Factor In Survival Following MYC Activation

The study reveal an essential role for activating transcription factor in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible kinase through uncharged transfer RNAs. For years, researchers have been trying to target a gene called MYC; that is knowing to drive tumor growth in multiple cancer types when it is mutating or over-expressing; but hitting that target successfully has proven difficult.

The pathway involves a protein called ATF4, and when it is blocking; it can cause cancer cells to produce too much protein and die. 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.

Transcription factors

MYC is a gene that controling normal cell growth; but when it is mutating or amplifying in cancer, it sets off a chain reaction that helping tumors grow uncontrollably. While there is currently no specific way to target it, previous research has focusing on blocking other steps in the chain as a workaround to impede tumor growth; in certain tumors, one of these steps is regulated by a kinase called PERK, which activates ATF4.

However, in this new study; they were 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. This study identifying this second kinase, which is knowing as GCN2.

Signal pathways converge

This study showing the alternative approach is to target ATF4 itself; since it is the point where both signal pathways converge; meaning there is less redundancy building in to allow cancer to survive. The findings also showing that ATF4 turns on the genes MYC needs for growth and also controls the rate at which cells make specific proteins called 4E-BP. ATF4 in cells or mice; they found tumor cells continued to build up those proteins and eventually died as a result of stress.

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; This study also finding that when tumors in humans are driving by MYC, ATF4 and its protein partner 4E-BP are also overly expressing; which is further evidence that these findings may point to an approach that could work for humans.