A hidden weakness in deadly cancers could lead to powerful new treatments
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- UCLA researchers found that small cell neuroendocrine cancers lacking the RB gene become critically dependent on the E2F3 protein to survive, across tumors originating in the lung, prostate, and ovary.
- Blocking E2F3 shut down tumor growth in laboratory models through synthetic lethality — cancer cells tolerate losing either gene alone, but not both at once.
- The team built new prostate cancer models by engineering normal human prostate cells with five cancer-causing genetic changes, including loss of RB and TP53, then growing them into organoids and mouse tumors.
- Genome-wide CRISPR screens flagged roughly 1,400 genes essential for cancer cell survival, with E2F3 standing out as a shared dependency across small cell cancers from different organs.
- Inhibiting the metabolic enzyme DHODH lowered E2F3 levels and slowed tumor growth — and DHODH-targeting drugs leflunomide and teriflunomide are already FDA-approved for autoimmune diseases.
- The study was published in PNAS by Dr. Owen N. Witte's group with first author Dr. Evan Abt; Witte noted survival statistics for these tumors are essentially the same as when he first saw them as a medical student over 50 years ago.
Why it matters: For patients with small cell neuroendocrine cancers of the lung, prostate, and ovary, treatment options have barely advanced in decades — Dr. Witte noted survival statistics are essentially unchanged from 50 years ago. Repurposing already-FDA-approved DHODH inhibitors could compress the path from lab discovery to clinical use, giving oncologists their first meaningful new mechanism against these tumors in a generation.
