‘Amazing discovery’: Approach may curb Myc levels, stop fast-growing cancers
Key takeaways:
- Inhibiting RMB42 disrupted production of Myc proteins in pancreatic cancer cells.
- This approach could curtail the growth of several cancer types.
A review paper published last year in European Journal of Medicinal Chemistry characterized Myc as the “oncogene from hell.”
It is overexpressed in more than 70% of cancer types and is a significant driver of proliferation.
“Myc is one of the worst oncogenes possible because it’s undruggable,” Davide Ruggero, PhD, professor of urology, Helen Diller family endowed chair in basic cancer research and principal investigator at Ruggero Lab at University of California, San Francisco, told Healio. “The more Myc you build, the cancer becomes more aggressive, metastatic.”
Myc inhibition has been characterized as the “Holy Grail” in research into many cancer types, such as prostate cancer.
Ruggero and colleagues may have found a way to do that through an RNA-binding protein in pancreatic cancer cells.
Early data showed disruption of RBM42 stopped cells from producing Myc proteins. This approach could benefit patients with pancreatic cancer and possibly other tumor types.
“There’s a lot of enthusiasm [and] a lot of excitement,” Ruggero said. “Identifying a regulator of Myc — such a powerful oncogene — is not only rewarding, but it’s an amazing discovery.”
Background
Approximately 42% of pancreatic ductal adenocarcinomas have high levels of Myc, according to study background.
These malignancies are “the most aggressive subtype” and are associated with the worst outcomes, Ruggero and colleagues wrote.
Scientists identified Myc in the 1970s, and they discovered the protein does not have to be mutated to become cancerous. Instead, it’s the continuous production that makes the protein dangerous.
Cancer cells can use Myc as resistance against treatments, as well.
“At the moment, there is enthusiasm to target another oncogene [in pancreatic cancer], KRAS,” Ruggero said. “There is a lot of emphasis to find the molecule that binds specifically to mutant KRAS. After patients started to take a KRAS inhibitor, there is some early response, but then all of them come back with more aggressive cancer. One of the mechanisms of resistance to KRAS [inhibitors] is the cancer starts to overexpress Myc. This is an example of how powerful Myc is. It’s not only a driver for cancer, but it’s one of the biggest problems for drug resistance. Cancer — almost an intelligent design — always figures out a way to come back even stronger, and often they use Myc.”
Most research into Myc has focused on expression at the mRNA level, but that might not be the most effective way, Ruggero said.
“How much transcription Myc you have, it doesn’t mean much, because you can have 2 billion molecules of an mRNA, but you make only one molecule of protein,” he added. “Our question was really to understand, if you have any mRNA, what is the mechanism that you go from Myc mRNA to Myc protein.”
Methods and results
Ruggero and colleagues used a CRISPR interference screen to investigate Myc translation in pancreatic cancer cells.
They discovered cells that had large amounts of Myc also had increased RMB42.
Further analysis showed RBM42 binds to a region of mRNA called 5’ untranslated region, which determines how much mRNA gets translated into proteins, causing more MYC proteins to be built.
When researchers inhibited RBM42 in mice, the cells kept producing Myc mRNA, but not Myc protein.
“Think about having a lot of Legos,” Ruggero said. “You put them all together. You create a huge structure where no one can go inside. RBM42 comes and takes apart all these pieces and remakes a different structure. Now, you have a huge door where everyone can go inside. RBM42 remodels the structure, and it brings the ribosomes to tell the cancer cell you have to make a lot of this [Myc] protein.”
Ruggero and colleagues further investigated in cells from patients with pancreatic cancer. Those who had high levels of RBM42 did worse and died faster than those who had lower expression.
RBM42 also increased translation of other “heavyweight” oncogenes, Ruggero said, such as EGFR and JUN.
“That is another important point to keep in mind,” Ruggero said.
‘Extremely valuable’
The next steps in research include developing compounds that could target RBM42.
“I think targeting RNA binding proteins is a new future,” Ruggero said.
Researchers are working on different models to examine RBM42 in other cancer types, too.
“I think this definitely can be extended to other cancers,” Ruggero said.
An RBM42 inhibitor likely would not be a monotherapy, but it could be used in combination with other treatments.
“Even if you don’t have the best compounds at the beginning, maybe we have something that targets 50% of the production of Myc. This is still good because Myc makes the cancer cell addicted to it,” Ruggero said. “Anytime you remove something from something that is addicted, you make the system suffer. Even reducing the Myc amount 20%, a cancer cell may suffer much more than normal cells. Even if we don’t know the perfect compounds, it still may be extremely valuable.”
References:
- Can scientists throw a wrench into cancer’s growth gears? Available at: https://www.ucsf.edu/news/2025/02/429416/can-scientists-throw-wrench-cancers-growth-gears. Published Feb. 4, 2025. Accessed March 3, 2025.
- Kovalski JR, et al. Nat Cell Biol. 2025;doi:10.1038/s41556-024-01604-7.
- Papadimitropoulou A, et al. Eur J Med Chem. 2024;doi:10.1016/j.ejmech.2024.116194.
For more information:
Davide Ruggero, PhD, can be reached at davide.ruggero@ucsf.edu.
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