“When I first encountered these tumors as a medical student more than 50 years ago, the survival statistics were essentially the same as they are today.” That is Dr. Owen N. Witte of UCLA, describing small cell neuroendocrine cancers, and it explains why his team’s latest result matters to oncologists.
The cancers can start in the lung, prostate or ovary. They grow fast and spread early. Most carry a lost RB gene, which normally keeps cell growth in check; without it, the cells multiply rapidly and shrug off many targeted drugs.
The study, published in Proceedings of the National Academy of Sciences, found that losing RB also leaves these cells leaning hard on a protein called E2F3. Cut E2F3 as well, and they cannot survive. Cancer cells can live without RB, the researchers found, but not without both. The principle is called synthetic lethality.
Building a model first
Realistic lab models have been the bottleneck, especially for small cell prostate cancer. Without them, nobody could say which genes these tumors depend on.
The UCLA group engineered normal human prostate cells with five major cancer-causing changes, including loss of RB and TP53. They grew the cells into organoids, then used them to produce tumors in mice. The result closely resembles human small cell prostate cancer. It builds on more than a decade of work in Witte’s laboratory.
Genome-wide CRISPR screens on those models looked at thousands of genes. Nearly 1,400 turned out to matter for keeping the cancer cells alive. Small cell cancers from different organs shared a strong dependence on E2F3. When the team lowered E2F3 in RB-deficient cells, the tumors stopped dividing and could no longer form clusters. Some cells died.
“It’s not that the two genes do the same thing,” said Witte, a senior author who holds the Presidential Chair in Developmental Immunology and is a member of the UCLA Health Jonsson Comprehensive Cancer Center. “But the combination of what they do together becomes essential for the cancer cell. Losing one gene may not matter much, but losing both has a dramatic effect on tumor growth.”
First author Dr. Evan Abt, an assistant professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, said the models “allowed us to uncover a genetic vulnerability that would have been very difficult to find otherwise.”
Existing drugs
No medicine targets E2F3 directly. So the team went around it. Inhibiting an enzyme called DHODH blocks a metabolic pathway that makes DNA building blocks, and that lowered E2F3 levels and slowed tumor growth.
DHODH inhibitors, including leflunomide and teriflunomide, are already FDA-approved for autoimmune diseases. Repurposing them could speed development. “What’s exciting is that our findings open the door to applying existing drugs in a new way,” Abt said.
The work is still at an early stage, done in laboratory models. Readers with a diagnosis should talk to their doctor about treatment options.
