UCLA researchers announced on Mar. 23 that they have discovered a potential new weakness in small cell neuroendocrine cancers, which could lead to improved treatment strategies for these aggressive tumors.
Small cell neuroendocrine cancers, which can develop in the lung, prostate, and ovary, are known for their rapid growth and resistance to existing therapies. These cancers often lack the RB gene, a protective factor that normally limits cell growth. The absence of RB allows cancer cells to multiply unchecked and evade many targeted treatments.
The study, published in the Proceedings of the National Academy of Sciences, found that cancer cells missing RB become highly dependent on another protein called E2F3 for survival. Laboratory experiments showed that blocking E2F3 halted tumor growth—a phenomenon described as "synthetic lethality." Senior author Dr. Owen N. Witte said, "Discovering a vulnerability like this opens the door to thinking about entirely new treatment strategies. That's especially important because there has not been a major change in how we treat these cancers for decades. 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."
To better understand these tumors' weaknesses, UCLA scientists developed new laboratory models by genetically altering normal human prostate cells with five key cancer-driving changes—including loss of RB and TP53—then growing them into organoids and using them to form tumors in mice. This allowed comprehensive genetic screening using CRISPR technology across thousands of genes.
The team identified nearly 1,400 genes important for cancer cell survival but found that dependence on E2F3 was shared among small cell cancers from different organs. Blocking E2F3 led to tumor cells failing to divide or form clusters—and sometimes dying outright—in laboratory studies.
Since no drugs currently target E2F3 directly, researchers tested whether inhibiting DHODH—an enzyme involved in DNA synthesis—could lower E2F3 levels and slow tumor growth instead. Drugs such as leflunomide and teriflunomide already approved by the Food and Drug Administration for autoimmune diseases may be repurposed based on this finding. Co-author Abt said: "What's exciting is that our findings open the door to applying existing drugs in a new way... By understanding how these cancers depend on E2F3, we can start to think about strategies that might work much more quickly in patients."
While still early-stage research, this discovery offers hope for developing new approaches against hard-to-treat small cell neuroendocrine cancers.
