Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade

A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3 in this cancer subtype. E2F3 dependency is linked to RB inactivation, an event that occurs nearly universally across small cell cancers.

The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung and adnexa (ovary and fallopian tube). 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 cancer proliferation in culture.