E2F3 amplification primes bladder cancer cells for premature mitosis

Unlike these lesions, E2F3 amplification drives persistent excessive E2F-dependent transcription through S and G2 phases. This oncogene is frequently amplified in for example bladder cancer, but its impact on the cancer cell cycle remains unclear.

Using isogenic bladder cancer models and patient data, we show that E2F3 amplification hyperactivates a mitotic gene expression program, including cyclin B1. This predisposes cells to unscheduled mitosis when the G2/M checkpoint is inhibited using the PKMYT1 inhibitor lunresertib, alone or in combination with low dosages of the WEE1 inhibitor zederosertib. E2F3-amplified cells acquired resistance to lunresertib by permanently reducing cyclin B1 expression, thereby preventing premature mitotic entry.