UCLA Researchers Uncover Genetic Vulnerability in Aggressive Cancers

UCLA researchers have identified a genetic vulnerability in aggressive small cell neuroendocrine cancers, which include tumors originating in the lung, prostate, and ovary. These cancers are characterized by rapid growth, early spread, and resistance to many treatments, often due to the loss of the protective RB gene.

New research, published in the journal Proceedings of the National Academy of Sciences, indicates that the absence of the RB gene makes cancer cells highly dependent on a protein called E2F3 for survival. Blocking E2F3 in laboratory studies effectively halted tumor growth, a phenomenon described as "synthetic lethality."

Dr. Owen N. Witte, the study's senior author, noted that this discovery offers new treatment strategy possibilities for cancers whose survival statistics have remained largely unchanged for decades.

Developing Novel Cancer Models

The research team developed new laboratory models by genetically altering human prostate cells to introduce five cancer-driving changes, including the loss of RB and TP53. These cells were grown as organoids and used to form tumors in mice, creating models that closely resemble human small cell prostate cancer.

Unveiling E2F3 Dependence

Using these models, genome-wide CRISPR screens identified nearly 1,400 genes critical for cancer cell survival. A strong dependence on E2F3 was observed across small cell cancers from different organs. Experiments demonstrated that reducing E2F3 levels in RB-deficient cancer cells led to a cessation of division, failure to form clusters, and cell death.

A Promising Therapeutic Avenue

As there are no direct E2F3-targeting drugs, researchers explored an alternative. They found that inhibiting the enzyme DHODH, which is involved in DNA building block synthesis, reduced E2F3 levels and slowed tumor growth. DHODH inhibitors, such as leflunomide and teriflunomide, are already FDA-approved for autoimmune diseases, potentially accelerating their application in cancer therapy.

Dr. Evan Abt, the first author, highlighted that these new model systems enabled the discovery of a genetic vulnerability that would have been difficult to identify otherwise.