A hidden weakness in deadly cancers could lead to powerful new treatments

Small cell neuroendocrine cancers can develop in the lung, prostate, and ovary. These fast-growing tumors tend to spread early and have remained among the hardest cancers to treat successfully.

A key feature of these cancers is the loss of a gene called RB. Under normal conditions, RB helps keep cell growth under control. When the gene is missing, cancer cells multiply rapidly and become resistant to many targeted therapies.

Now, a new study published in Proceedings of the National Academy of Sciences suggests that losing RB also creates an unexpected vulnerability that researchers believe could become a powerful treatment target.

A Hidden Dependency in Deadly Cancers

The UCLA team discovered that cancer cells lacking RB become heavily dependent on a protein called E2F3 to survive. In laboratory experiments, blocking E2F3 prevented tumor growth through a process known as "synthetic lethality."

In simple terms, cancer cells can survive without RB, but they cannot survive when both RB and E2F3 are lost. Removing E2F3 alongside the missing RB exposes a critical weakness that researchers believe could be exploited with future therapies.

"Discovering a vulnerability like this opens the door to thinking about entirely new treatment strategies," said study senior author Dr. Owen N. Witte, who holds the Presidential Chair in Developmental Immunology in the Department of Microbiology, Immunology, and Molecular Genetics and is a member of the UCLA Health Jonsson Comprehensive Cancer Center. "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."

Building Better Models To Study Small Cell Cancer

Progress against small cell neuroendocrine cancers, especially those that develop in the prostate, has been slowed by the lack of realistic laboratory models. Without them, scientists have struggled to identify the genes these tumors rely on and uncover their biological weaknesses.

To overcome that challenge, the UCLA researchers engineered normal human prostate cells with five major cancer-causing genetic changes, including the loss of RB and TP53. The cells were grown into organoids and then used to produce tumors in mice, creating models that closely resemble human small cell prostate cancer.

The work builds on more than a decade of research by Witte's laboratory to develop specialized models of small cell neuroendocrine prostate cancer.

CRISPR Screens Reveal a Shared Weakness

Using these models, the team performed genome-wide CRISPR screens that examined thousands of genes to determine which ones were essential for cancer cell survival.

The researchers identified nearly 1,400 genes that play important roles in keeping the cancer cells alive. Among the most significant discoveries was that small cell cancers from different organs all shared a strong dependence on E2F3.

When the scientists reduced E2F3 levels in RB-deficient cancer cells, the tumors stopped dividing, could no longer form clusters, and in some cases died completely.

"It's not that the two genes do the same thing," said Witte, who is also the founding director emeritus of the UCLA Broad Stem Cell Research Center and co-director of the Parker Institute of Cancer Immunotherapy Center at UCLA. "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."

"These new model systems allowed us to uncover a genetic vulnerability that would have been very difficult to find otherwise," added first author Dr. Evan Abt, an assistant professor of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA.

Existing FDA-Approved Drugs May Offer a Shortcut

Because no medicines currently target E2F3 directly, the researchers looked for another way to exploit the cancer's weakness.

They found that blocking a metabolic pathway involved in producing DNA building blocks by inhibiting an enzyme called DHODH lowered E2F3 levels and slowed tumor growth.

That finding is especially intriguing because DHODH inhibitors, including leflunomide and teriflunomide, are already FDA-approved to treat autoimmune diseases. Repurposing existing medications could potentially speed the development of new therapies for patients with these cancers.

"What's exciting is that our findings open the door to applying existing drugs in a new way," Abt said. "By understanding how these cancers depend on E2F3, we can start to think about strategies that might work much more quickly in patients."

Although the research remains in its early stages, the findings provide important new insight into how these aggressive cancers survive and point toward a promising new direction for future treatments.

Other UCLA authors are Liang Wang, Grigor Varuzhanyan, Jack Freeland, Tian He, Guadalupe M. Peña-Garcia, Lauryn Ruegg, Jami McLaughlin, Donghui Cheng, Nikolas G. Balanis, Chia-Chun Chen, Sanaz Memarzadeh, Caius G. Radu and Thomas G. Graeber.