UCLA study finds that small cell neuroendocrine tumors depend on a specific protein to grow, offering a potential path for new treatments.
RT’s Three Key Takeaways:
Genetic Dependency Identified: Researchers found that small cell neuroendocrine cancers, including lung and prostate tumors, become highly dependent on the E2F3 protein after losing the protective RB gene.
Halting Tumor Growth: Laboratory experiments showed that reducing E2F3 levels in cancer cells deficient in the RB gene stopped the tumors from dividing and led to cell death.
Potential for Drug Repurposing: Inhibiting the DHODH enzyme with medications already approved by the Food and Drug Administration (FDA) lowered E2F3 levels, suggesting a faster route to clinical application for these aggressive cancers.
UCLA researchers have identified a genetic vulnerability in small cell neuroendocrine cancers, offering a potential new strategy for targeting aggressive tumors that arise in the lung, prostate, and ovary, according to a study published in Proceedings of the National Academy of Sciences.
Small cell neuroendocrine cancers are known for rapid growth, early metastasis, and resistance to many standard therapies. A defining characteristic of these tumors is the loss of the RB gene, which normally functions as a brake on cell growth. Without this gene, cancer cells multiply rapidly. However, research suggests this genetic loss creates an unexpected dependency on a protein called E2F3.
“Discovering a vulnerability like this opens the door to thinking about entirely new treatment strategies,” said Owen N Witte, presidential chair in developmental immunology and member of the UCLA Health Jonsson cancer center, in a news release. “That’s especially important because there has not been a major change in how we treat these cancers for decades.”
To identify these weaknesses, the UCLA team developed new laboratory models by genetically altering human prostate cells to resemble human small cell prostate cancer. Using genome-wide CRISPR screens, the researchers tested thousands of genes to find which ones the cancer cells required for survival. They discovered that small cell cancers from various organs share a strong dependence on E2F3.
In laboratory experiments, the researchers found that reducing E2F3 levels in RB-deficient cancer cells caused tumors to stop dividing and, in some cases, die. Scientists refer to this relationship—where the loss of two specific genes together causes cell death while the loss of either alone does not—as “synthetic lethality.”
Because no existing drugs target E2F3 directly, the team explored inhibiting the DHODH enzyme, which is involved in a metabolic pathway for DNA building blocks. They found that blocking DHODH lowered E2F3 levels and slowed tumor growth. Notably, DHODH inhibitors such as leflunomide and teriflunomide are already approved by the Food and Drug Administration (FDA) for autoimmune diseases.
“What’s exciting is that our findings open the door to applying existing drugs in a new way,” said Evan Abt, assistant professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, in a news release. “By understanding how these cancers depend on E2F3, we can start to think about strategies that might work much more quickly in patients.”