Nucleic Acids Research publication: New study reveals how targeting transcription termination can boost the impact of WEE1 inhibitors in cancer therapy
Scientists from the Department of Radiation Biology report a new strategy to enhance the effectiveness of WEE1 inhibitor–based cancer treatment, published recently in Nucleic Acids Research. The study shows that disrupting transcription termination — the process that properly stops RNA synthesis — significantly increases DNA damage and cancer cell death when combined with the WEE1 inhibitor adavosertib.
WEE1 inhibition pushes cancer cells into excessive DNA replication, creating replication stress. Although multiple WEE1 inhibitors are currently being evaluated in clinical trials, how to best use them for cancer treatment remains unclear. The researchers found that transcription termination normally protects cells by preventing harmful collisions between transcription and replication. When this safeguard is weakened, these conflicts intensify, leading to greater DNA damage.
Using genetic and pharmacological approaches, the team showed that depletion of several termination factors (PNUTS, WDR82, XRN2, CPSF73, and DDX5) increased S-phase DNA damage after WEE1 inhibition. Defective termination caused “read-through” transcription, allowing RNA polymerase to extend beyond normal stop sites and collide with replication forks. Dampening active transcription reduced this damage, linking elongating RNA polymerase to the toxic effects.
Importantly, combining adavosertib with the CPSF73 inhibitor JTE-607 synergistically reduced survival of prostate cancer cells. Elevated CPSF73 expression was also associated with more aggressive prostate tumors, highlighting potential clinical relevance.
These findings identify transcription termination as a therapeutic vulnerability and support combination strategies pairing WEE1 inhibitors with drugs that exacerbate transcription–replication conflicts, particularly in aggressive and treatment-resistant cancers.
Links:
The Nucleic Acids Research article:
Landsverk HB, Sandquist LE, Bay LTE, Hauge S, van Bijsterveldt L, Lindbergsengen L, Lund-Andersen C, Kanduri C, Lyng H, Fjeldbo CS, Hompland T, Humphrey TC, Syljuåsen RG (2026)
Transcription termination counteracts DNA damage after WEE1 inhibition
Nucleic Acids Res, 54 (3)
DOI 10.1093/nar/gkaf1487, PubMed 41569153
OUS - Radiation Biology and DNA Damage Signaling (Syljuåsen)