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Finding Sorafenib-Responding Signature in Hepatocellular Carcinoma (HCC)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285625 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:BACKGROUND & AIMS: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). In early-stage HCC, survival benefits of resection/local ablation are compromised by high recurrence rates (70% at 5-years). In this setting, the phase-3 STORM-trial did not achieve its primary end-point of improving recurrence-free-survival (RFS) comparing sorafenib to placebo as adjuvant treatment. Herein we present results of the biomarker companion study BIOSTORM in which we define predictors of recurrence prevention with sorafenib and prognostic factors with B-level of evidence. METHODS: Tumor tissue from 188 patients randomized to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene-expression profiling, targeted exome sequencing (18 known onco-drivers), immunohistochemistry (pERK, pVEGFR2, Ki67), FISH (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time-to-recurrence equaled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinical and pathological characteristics of STORM patients. None of the biomarkers tested that are known to be related to angiogenesis and proliferation, or previously proposed gene-signatures, or mutations predicted sorafenib benefit. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p-of-interaction=0.04). These sorafenib responders were significantly enriched in CD4+ T, B, and cytolytic Natural Killer cells, and showed absence of activated macrophages and other components of adaptive immunity. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSIONS: In BIOSTORM, hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene-signatures predicted sorafenib benefit. A newly generated multi-gene signature associated with improved RFS on sorafenib warrants further validation. KEYWORDS: sorafenib; tyrosine-kinase inhibitor; trial enrichment; stratification.

Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

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Finding Sorafenib-Responding Signature in Hepatocellular Carcinoma (HCC)

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