Science Signaling | Insilico Medicine Contributes to Research Using AI to Reveal NDRG1-Associated DNA Repair Mechanisms and Potential Synthetic Lethal Effects in Colorectal Cancer

Summary

A joint study by Insilico Medicine, the University of Copenhagen, and academic partners identifies NDRG1 as a key regulator of DNA damage repair, demonstrating that targeting this pathway via the antimalarial drug quinacrine triggers synthetic lethality in specific cancer subtypes. Insilico Medicine (HKEX:3696, "Insilico"), a clinical-stage biotechnology company pioneering generative artificial intelligence (AI) for drug discovery and development, announced publication of a new study in Science Signaling. The paper details how computational biology and experimental research converged to uncover a novel target in cancer DNA damage repair centered on the stress-response protein NDRG1. Led by researchers at the University of Copenhagen in collaboration with Insilico Medicine and international partners, the multidisciplinary study combined computational transcriptomic analyses, high-content genetic screening, molecular biology, and large-scale cancer cell profiling. The team demonstrated that pharmacological or genetic disruption of the NDRG1–VCP interaction impairs the recruitment of key DNA repair proteins, triggering synthetic lethality in specific cancer subtypes—most notably colorectal cancers harboring MLH1 or PARP3 mutations. “DNA damage repair is essential to cell survival, making it an attractive target for cancer therapy. Mkrtchyan et al. identified a therapeutically exploitable role for the stress-response protein NDRG1 in the DNA damage response (DDR). High-throughput screens revealed that high NDRG1 expression in cancer cell lines correlated with sensitivity to the antimalarial drug quinacrine, which impaired the ubiquitylation-dependent recruitment of a critical DDR protein to sites of DNA damage. Colorectal cancer cells with mutations in the DNA repair–associated genes MLH1 and PARP3 were particularly sensitive to quinacrine or NDRG1 knockdown. The findings reveal potential strategies to target the DDR based on NDRG1 expression. ” summarized by Leslie K. Ferrarelli, Senior Editor at Science Signaling From Computational Hypothesis to Biological Discovery Cancer cells frequently become dependent on the DNA repair pathways that remain functional after accumulating genetic alterations. Identifying these dependencies can reveal new therapeutic opportunities and help guide precision medicine approaches. The study combined computational transcriptomic a…