Comprehensive multi-omics analyses expose a precision therapy strategy that targets replication stress in hepatocellular carcinoma using WEE1 inhibition

Our findings provide promising insights into the precise therapeutic targeting of RS in HCC at both the proteomic and transcriptomic levels. Furthermore, our study highlights the potential of combining oxaliplatin with adavosertib as a treatment approach for HCC. In this study, we analyzed 178 and 94 pairs of clinical HCC samples using proteomic and transcriptomic sequencing, respectively. We discovered that the subtype characterized by high proliferation had the worst prognosis and highest RS level. Drug screening revealed that oxaliplatin promotes RS accumulation in HCC, but its resistance remains a challenge. Through unbiased CRISPR deletion-gene screening, WEE1 was identified as a lethal target of oxaliplatin. The WEE1 inhibitor adavosertib inhibits oxaliplatin-induced DNA repair, leading to lethal DNA damage accumulation. Furthermore, our clustering analysis based on RS levels demonstrated that HCC patients with high RS levels have poorer prognoses and be more beneficial from adavosertib and oxaliplatin combination therapy. These findings support an individualized treatment approach for HCC targeting RS based on WEE1 Inhibition.