Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade
Abstract
Small cell carcinoma is a highly lethal cancer variant often found with neuroendocrine (NE) features, as exemplified by small cell lung cancer and small cell NE prostate cancer (SCPC). 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Evan R. Abt
Department of Molecular and Medical Pharmacology, University of California
Liang Wang
Grigor Varuzhanyan
Department of Microbiology, Immunology, and Molecular Genetics, University of California
Jack Freeland
Department of Molecular and Medical Pharmacology, University of California
Tian He
Department of Molecular and Medical Pharmacology, University of California
Guadalupe M. Peña-Garcia
Department of Microbiology, Immunology, and Molecular Genetics, University of California
Lauryn Ruegg
Department of Obstetrics and Gynecology, University of California
Jami McLaughlin
Department of Microbiology, Immunology, and Molecular Genetics, University of California
Donghui Cheng
Department of Microbiology, Immunology, and Molecular Genetics, University of California
Nikolas G. Balanis
Department of Molecular and Medical Pharmacology, University of California
Chia-Chun Chen
Department of Chemistry
Yang Xu
Yi Xing
School of Energy and Environmental Engineering
Sanaz Memarzadeh
Jonsson Comprehensive Cancer Center, University of California at Los Angeles
Caius G. Radu
Department of Molecular and Medical Pharmacology, University of California
Thomas G. Graeber
Owen N. Witte
Department of Molecular and Medical Pharmacology, University of California