How Scientists Are Disrupting Cancer's Inner Workings
Imagine a factory assembly line running out of control, producing products at a dangerous, unsustainable rate. Now picture that same scenario unfolding inside your cells—that's essentially what happens in many cancers. For decades, cancer treatment has focused on disabling specific mutated proteins found in tumors, much like fixing broken parts on that runaway assembly line. But cancer has proven notoriously adept at finding workarounds, developing resistance, and continuing its destructive growth 2 7 .
Now, scientists at UC San Francisco have developed a radically different approach. Instead of targeting the broken parts, they're learning how to throw a wrench directly into the gears of cancer's production machinery itself.
Their target? A notorious cancer-driving protein called MYC that runs wild in 70% of all cancers. This isn't about fixing broken components—it's about shutting down the entire dangerous production line at its source 2 7 .
Involve MYC protein dysregulation
Targeting protein production rather than mutations
Pioneering work on translation control
MYC represents one of the most frustrating puzzles in cancer biology. First identified in the 1970s by UCSF Nobel Laureates Michael Bishop and Harold Varmus, MYC is actually a normal cellular protein that plays crucial roles in healthy cell function. It only becomes dangerous when produced in excessive quantities. Unlike other cancer drivers that require specific mutations, MYC can fuel cancer development simply through overproduction—cells become cancerous by producing MYC unceasingly, even without mutations in the MYC gene itself 2 7 .
To understand why MYC has been so difficult to target, we need to understand how proteins are made inside cells. The process operates much like a sophisticated factory:
The cell uses instructions stored in the MYC gene to create a blueprint called mRNA
The cell's protein factories (ribosomes) use this mRNA blueprint to manufacture MYC protein 2
Previous attempts to target MYC focused on the first step—trying to prevent the creation of the mRNA blueprint. But cancer cells often bypass these restrictions through alternative pathways. The UCSF team decided to try a different strategy: instead of interfering with the blueprint creation, they would target the translation process where the actual protein assembly occurs 2 .
Joanna Kovalski, a postdoctoral scholar in the Ruggero Lab, embarked on a systematic search for factors that influence how much MYC protein cancer cells produce. Using an advanced gene-editing method called CRISPRi, she screened for proteins that affected MYC production. The results were surprising—the screen pointed to a relatively obscure protein called RBM42 that hadn't attracted much attention in cancer research until now 2 .
When Kovalski examined genomic data from pancreatic cancer patients, the connection became even clearer: tumors with abundant RBM42 also had high levels of MYC. Most importantly, patients with high levels of both proteins had significantly worse outcomes, suggesting this partnership was driving some of the most aggressive cancers 2 7 .
Further experiments revealed the remarkable mechanism by which RBM42 controls MYC production. When researchers disrupted RBM42, cancer cells continued to produce MYC mRNA blueprints normally—but suddenly stopped making the actual MYC protein. This indicated that RBM42 operated exclusively in the second phase of protein production: the translation of mRNA blueprints into finished proteins 2 .
RBM42 essentially hijacks the cellular machinery to give MYC special treatment. It reshapes the MYC mRNA blueprint to make it more efficient for ribosomes to process, then directs these optimized blueprints straight to the protein factories.
The result? Ribosomes churn out excessive amounts of MYC, fueling uncontrolled cancer growth 2 .
"Proteins like RBM42 and MYC exist in every cell but are normally restrained," said Davide Ruggero, PhD, senior author of the study. "During cancer, we saw that RBM42 behaved quite differently, hijacking the ribosomes to work with these specific mRNAs and do the cancer's bidding" 2 .
The research team designed a comprehensive series of experiments to validate their discovery and explore its therapeutic potential:
Using CRISPRi technology to systematically disable genes in pancreatic cancer cells to identify which affect MYC production 2
Analyzing genomic data from pancreatic cancer patients to correlate RBM42 and MYC levels with patient outcomes 2
The experimental results demonstrated a dramatic effect when RBM42 was disrupted. In both petri dishes and mice, removing RBM42 caused ribosomes to stop producing MYC, and pancreatic tumors ceased their aggressive growth.
| Patient Group | RBM42 Level | MYC Level | 5-Year Survival |
|---|---|---|---|
| Group 1 | Low | Low | 45% |
| Group 2 | Medium | Medium | 28% |
| Group 3 | High | High | 12% |
The most significant finding was that disrupting RBM42 effectively stopped MYC production without affecting the blueprints for other essential proteins, suggesting this approach could have fewer side effects than conventional cancer treatments 2 7 .
MYC first identified as a normal protein that can cause cancer when dysregulated by Bishop and Varmus (UCSF)
Initial evidence of translation control importance in cancer by Ruggero Lab (UCSF)
RBM42 identified as key regulator of MYC production in CRISPR screen by Kovalski et al.
Therapeutic disruption of RBM42 shown to stop tumor growth in models by Kovalski, Ruggero et al.
Breaking new ground in cancer biology requires sophisticated tools. Here are the key research reagents and materials that made this discovery possible, which could become the foundation for future cancer therapies:
A modified version of CRISPR gene-editing technology that allows researchers to temporarily "turn off" genes without permanently altering DNA. This was essential for screening which genes affected MYC production 2 .
Collections of genetic information from cancer patients that allowed researchers to correlate RBM42 and MYC levels with disease outcomes 2 .
High-resolution imaging technologies that enabled scientists to visualize RBM42 and MYC proteins interacting within tumor cells from patient biopsies 2 .
Methods for studying the entire complement of proteins in cells, crucial for understanding how disrupting RBM42 affected overall protein production beyond just MYC 2 .
The discovery of RBM42's role in controlling MYC production represents more than just another incremental advance in cancer biology—it potentially opens an entirely new front in the war against cancer. By targeting the translation process rather than individual mutated proteins, scientists may have found a way to hit cancer at its fundamental production infrastructure 2 7 .
"RBM42 really seems to be the Achilles' heel for some of the worst cancers," said Ruggero. The researchers believe that small molecules could be developed to disrupt the RBM42-MYC interaction, effectively acting as molecular wrenches that jam cancer's gears 2 7 .
of cancers potentially vulnerable
side effects expected
therapeutic approach
This approach could be particularly powerful because it doesn't rely on cancer having specific mutations. Any cancer dependent on MYC overproduction—which includes 70% of all cancers—potentially becomes vulnerable to this strategy. The team is now working to develop drugs that can achieve in patients what they've demonstrated in the lab: stopping MYC production by targeting RBM42 2 .
"Translation control deserves to be front and center in our efforts to treat cancer," Kovalski said. "We now have great footing to interfere with the fastest-growing cancers and make a difference for patients" 2 .
As research continues, this "wrench in the gears" approach may eventually offer new hope for patients with some of the most aggressive and treatment-resistant cancers, turning cancer's own production machinery against itself in the battle to save lives.