New genetic discovery could spell this aggressive cancer’s downfall
A newly identified vulnerability of small cell neuroendocrine carcinoma could represent a potential treatment strategy for these aggressive and difficult-to-treat cancers.
University of California, Los Angeles (UCLA; CA, USA), researchers have revealed a chink in the armor of small cell neuroendocrine cancers, potentially opening up a new route to therapies for these tough-to-treat tumors. By establishing cell lines and conducting genome-wide CRISPR screens, the team identified a key protein, which, when inhibited in in vivo experiments, halted tumor growth, making it a promising target for future research.
Small cell carcinoma is a highly lethal cancer, frequently characterized by neuroendocrine features, which can arise in multiple tissues, including the lung, prostate and colon, often as a mechanism of resistance to targeted therapies. Patient prognosis is particularly poor, in part due to a lack of treatment options that leverage knowledge of the genetic changes driving the disease.
“There has not been a major change in how we treat these cancers for decades,” decried study senior author Owen N. Witte. “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.”
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Inactivation of the tumor suppressor genes RB and TP53 is almost universal across small cell cancers, and this may give rise to common vulnerabilities that can be exploited for therapeutic targeting. Unfortunately, reliable non-pulmonary small cell cancer models are scarce, which limits the scope of this approach.
To address this gap, the researchers established a series of cell lines with the transcriptional and phenotypic characteristics of human small cell neuroendocrine prostate cancer. Starting with human prostate basal cells from multiple donors, they introduced five genetic alterations, including loss of TP53 and RB function, before culturing the cells as organoids and propagating them as tumors in immunodeficient mice.
Cell lines derived from these tumors were then cultured and used in genome-wide, proliferation-based CRISPR knockout screens to identify genes essential for the cancer cells’ survival. Doing so highlighted the transcription factor E2F3 as a particular vulnerability in this cancer subtype.
Subsequent validation experiments revealed a synthetic lethal interaction between inhibition of E2F3 and loss of RB. In RB-deficient cancer cells, E2F3 inhibition restrained cell cycle progression, proliferation and tumor growth. Moreover, in vivo experiments in immunodeficient mice with RB knocked out and E2F3 knocked down by shRNAs resulted in a marked suppression of tumor growth compared to controls.
To demonstrate how this discovery could be used for drug development, the team inhibited a key enzyme (DHODH) in the de novo pyrimidine synthesis pathway, which limited E2F3 expression and suppressed small cell carcinoma proliferation in culture. This represents a promising avenue for therapeutic exploration, especially given that a number of DHODH inhibitors have already been FDA-approved for autoimmune conditions.
“What’s exciting is that our findings open the door to applying existing drugs in a new way,” first author Evan Abt announced. “By understanding how these cancers depend on E2F3, we can start to think about strategies that might work much more quickly in patients.”