In a new study, researchers from the Institute of Biochemistry at the University of Kiel have found a way to inhibit the function of the cancer-causing protein MYC. This could be used to develop new drugs. The relevant research results were recently published in the journal Gut, with the title of the paper "Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2".
The MYC gene and the protein produced from it are key drivers of many cancers. "It is indeed one of the most important oncogenes in humans, if not the most important one," says Professor Elmar Wolf, Director of the Institute of Biochemistry at the Medical Faculty of Medicine at the University of Kiel. That is why scientists worldwide are looking for possible ways to switch off this oncogene in order to develop new approaches to treat cancer. However, no inhibitors are currently available for clinical use.
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Since it is difficult to target MYC directly, Wolf and his team are pursuing an indirect approach via essential binding partners. This is because the cancer-promoting function of MYC is transmitted by binding to other proteins. Wolf and his team have identified one of these essential binding partners in cell cultures and animal models of pancreatic cancer.
The new study demonstrates that only a very small number of MYC binding partners are important for the progression of pancreatic cancer, and one of these is the protein RUVBL1. "Compared to the other binding partners studied, the loss of this protein most restricted the tumor growth of pancreatic cancer cells," explains Markus Vogt, first author of the paper and a doctoral student in Wolf's team. "Switching off RUVBL1 significantly reduced the size of pancreatic tumors and enabled the migration of immune cells into the tumors."
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This discovery was preceded by a great deal of work. First, mass spectrometry was used to determine which proteins bind to MYC. The results revealed 90 proteins. Then, each of these 90 binding partners was investigated to determine which one was important for tumor growth. To do this, they constructed a system with which the expression of each of these proteins could be switched off at the genetic level. This screen was performed in cultured cancer cells and in animal models of pancreatic cancer (PDAC). The experiments in the animal models were decisive.
"This is because many MYC binding partners turned out to be important for PDAC cells in culture, but not in vivo," emphasizes Vogt. The best binding partner they screened was the protein RUVBL1. They then analyzed it more closely in cell cultures. Subsequently, they used animal models to test whether switching off RUVBL1 actually slows tumor growth or whether existing tumors regress.
Figure 1. Genetic dropout screens reveal differential dependence on MYC binding partners in pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo. (Vogt M, et al. 2024)
"We used mainly genetic approaches to block the production of this protein. This had a therapeutic effect. The tumors regressed and the immune system was activated," explains Wolf. He speculates that this effect is based on the fact that immune cells migrate into the tumor. Pancreatic tumors in mice, like in humans, contain only a few immune cells and are therefore considered immunologically "cold tumors." Therefore, most patients with pancreatic cancer cannot benefit from immunotherapy. "We speculate that drugs targeting the MYC-RUVBL1 axis could make pancreatic tumors susceptible to immunotherapy," says Wolf.
Data from human tumors confirm the importance of this protein in pancreatic cancer. According to these data, the level of RUVBL1 protein is increased in tumors compared to normal healthy tissue. It coincides with the expression level of MYC.
Some tumors have relatively low levels of RUVBL1 protein, and at the same time they also have low levels of MYC protein. Tumors with high levels of RUVBL1 also have high levels of MYC. In addition, RUVBL1 appears to be an indicator of tumor aggressiveness, because tumors with high amounts of RUVBL1 have a higher mortality rate than tumors with low amounts of RUVBL1. The researchers are confident that RUVBL1 is a good target for drug treatment of pancreatic cancer.
Reference
Vogt M, et al. Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2. Gut, 2024.