A recent pre-print study, published on December 24 2024 on The Journal of Clinical Investigation, is exploring new ways to treat castration-resistant prostate cancer (CRPC) by focusing on DNA repair genes (DRG) beyond the well-known homologous recombination repair (HRR) genes.

This research used CRISPR/Cas9 screens in prostate cancer cell lines, combined with PARP inhibitor (PARPi) treatment. The study found that LIG1, EME1, and FAAP24 losses act as PARPi sensitizers, with these genes being deficient in 3 to 6% of CRPC patients. The research indicates that inactivating LIG1 and PARP together causes a synthetic lethality (SL) effect, which leads to replication stress, DNA double-strand breaks, and ultimately cell death (apoptosis).

This SL effect is not limited to prostate cancer and has also been observed in other tumor types, including lung, breast, and colorectal cancers, suggesting a broad applicability. Researchers believe this approach could be expanded to LIG1-functional tumors using a pharmacological combination approach. Additionally, the sensitivity of LIG1-deficient cells to PARPi was confirmed in vivo.

The study underscores the importance of determining LIG1 status, as well as other non-HRR DRGs, for stratifying CRPC patients and expanding their treatment options. Given that this study is currently in pre-print, it’s worth keeping an eye out for the published version. This research could potentially allow for more personalized and effective cancer treatments by targeting specific genetic vulnerabilities within tumors.

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