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A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3. E2F3 dependency is linked to RB inactivation, a near universal occurrence across small cell cancers. The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung, and adnexa. In RB-deficient cancer cells, E2F3 inhibition restrains cell cycle progression, proliferation, and tumor growth in vivo. Inhibition of de novo pyrimidine synthesis limits E2F3 expression and suppresses small cell carcinoma proliferation in culture. Directly or indirectly targeting E2F3 to leverage a pan-cancer synthetic lethality resulting from RB inactivation represents a potential treatment strategy.<\/jats:p>","DOI":"10.1073\/pnas.2532814123","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:42:33Z","timestamp":1774028553000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3160-7134","authenticated-orcid":false,"given":"Evan R.","family":"Abt","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, University of California","place":["Los Angeles"]},{"name":"Jonsson Comprehensive Cancer Center, The David Geffen School of Medicine, University of California","place":["Los 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