Genetic Weakness Offers Hope in Fighting Deadly Cancers

UCLA researchers uncover a hidden vulnerability in some of the deadliest cancers that could lead to new treatment strategies.

Mar. 24, 2026 at 5:38am

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Researchers at UCLA have discovered a genetic weakness in some of the most aggressive and treatment-resistant cancers, including small cell neuroendocrine cancers that can arise in the lung, prostate, and ovary. These cancers are defined by the loss of a protective gene called RB, which normally acts as a brake on cell growth. The team found that when RB is missing, the cancer cells become highly dependent on a protein called E2F3 to survive. Blocking E2F3 effectively halted tumor growth in laboratory studies, revealing a potential new treatment strategy through "synthetic lethality" - exploiting the cancer's reliance on E2F3 when RB is absent.

Why it matters

Small cell neuroendocrine cancers are among the deadliest and most difficult to treat, with survival rates that have remained essentially unchanged for decades. Discovering a genetic vulnerability like the dependence on E2F3 when RB is lost opens the door to entirely new treatment approaches that could significantly improve outcomes for patients with these aggressive tumors.

The details

The UCLA team developed new laboratory models of small cell prostate cancer by genetically altering normal human prostate cells and introducing key cancer-driving changes, including the loss of RB and TP53. Using these models, they performed genome-wide CRISPR screens to identify the genes the cancer cells depend on most for survival, finding nearly 1,400 genes important for cell survival but a strong dependence specifically on E2F3. When they blocked E2F3 in RB-deficient cancer cells, the tumors stopped dividing, failed to form clusters, and in some cases, died. This vulnerability means the cancer can survive the loss of RB alone but collapses when E2F3 is also blocked.

  • The research was published in the journal Proceedings of the National Academy of Sciences on March 24, 2026.

The players

Dr. Owen N. Witte

The senior author of the study, he holds the Presidential Chair in Developmental Immunology in the Department of Microbiology, Immunology, and Molecular Genetics at UCLA and is a member of the UCLA Health Jonsson Comprehensive Cancer Center.

Dr. Evan Abt

The first author of the study, he is an assistant professor of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA.

UCLA

The university where the research was conducted.

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What they’re saying

“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.”

— Dr. Owen N. Witte, Senior author of the study

“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.”

— Dr. Evan Abt, First author of the study

What’s next

The researchers plan to further investigate the potential of targeting the E2F3 pathway or the DHODH metabolic pathway as new treatment strategies for small cell neuroendocrine cancers.

The takeaway

This research uncovers a critical genetic vulnerability in some of the deadliest and most treatment-resistant cancers, opening up new possibilities for developing more effective therapies that could significantly improve outcomes for patients with these aggressive tumors.