Finding Sorafenib-Responding Signature in Hepatocellular Carcinoma (HCC)

Sorafenib has been a cornerstone in hepatocellular carcinoma (HCC) therapy; however, its efficacy is limited, and identifying patients that will respond to sorafenib is challenging. Gene expression data from 33 HCC tumors treated with sorafenib were analyzed to construct a prediction model aimed at identifying patients with greater benefit from sorafenib treatment. The analysis of transcriptome data revealed a 50-gene signature, KUSS50 (Korea University Sorafenib Signature with 50 genes), that exhibited high predictive power in identifying patients responded to sorafenib treatment in a training cohort. Extensive validation across 2 independent cohorts (IMbrave150 and BIOSTORM) given sorafenib demonstrated KUSS50's high specificity in predicting sorafenib response. Genomic analyses identified distinct molecular characteristics linked with KUSS50 subtypes, including an increased mutation rate and activation of ferroptosis, suggesting increased baseline ferroptotic activity in HCCs, which may sensitize them to sorafenib. The benefit subtype also overlapped with those in previously defined genomic HCC subtypes associated with stemness and aggressiveness. Conversely, the non-benefit subtype correlated with -catenin mutations and increased tumor purity, underscoring the biological significance of the signature. In conclusion, KUSS50 is a clinically actionable biomarker for optimizing HCC patient selection for treatment with sorafenib, providing an opportunity to improve outcomes. Further exploration of KUSS50's underlying biology, particularly the involvement of ferroptosis in sorafenib sensitivity, could provide additional therapeutic insights.