Scientists at UCLA have pinpointed a hidden vulnerability in certain highly aggressive and hard-to-manage cancers, sparking optimism for a novel approach to combat tumors that have defied treatment for decades. Small cell neuroendocrine cancers can arise in the lung, prostate, and ovary. These rapidly expanding tumors often metastasize early and have remained among the most difficult cancers to cure effectively. 
A defining characteristic of these malignancies is the loss of a gene known as RB. Under normal circumstances, RB assists in regulating cell growth. When this gene is absent, cancer cells proliferate quickly and develop resistance to numerous targeted treatments. Now, a fresh study released in Proceedings of the National Academy of Sciences indicates that the loss of RB also generates an unforeseen susceptibility that scientists think could evolve into a formidable treatment target.
The UCLA group found that cancer cells without RB become critically reliant on a protein named E2F3 to live. In lab trials, inhibiting E2F3 halted tumor expansion via a mechanism known as "synthetic lethality." In straightforward terms, cancer cells can endure without RB, yet they cannot survive if both RB and E2F3 are absent. Eliminating E2F3 in addition to the missing RB reveals a crucial frailty that researchers believe could be leveraged with upcoming 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." Advancement against small cell neuroendocrine cancers, particularly those originating in the prostate, has been hindered by the absence of practical laboratory models. Lacking these, scientists have found it hard to identify the genes these tumors depend on and reveal their biological frailties. 
To surmount that obstacle, the UCLA scientists modified normal human prostate cells with five primary cancer-inducing genetic alterations, including the loss of RB and TP53. The cells were cultivated into organoids and subsequently used to generate tumors in mice, establishing models that closely mimic human small cell prostate cancer. The effort builds upon over a decade of investigation by Witte's lab to create specialized models of small cell neuroendocrine prostate cancer. Using these models, the team conducted genome-wide CRISPR screens that analyzed thousands of genes to determine which were vital for cancer cell survival. The scientists identified nearly 1,400 genes that play crucial roles in maintaining cancer cell life. Among the most notable findings was that small cell cancers from various organs all shared a strong reliance on E2F3.