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Endogenous protein S100A14 stabilizes glutaminase to render hepatocellular carcinoma resistant to sorafenib

ABSTRACT: Many cases of advanced hepatocellular carcinoma (HCC) are resistant to the widely used drug sorafenib, which worsens prognosis. While many studies have explored how acquired resistance emerges during drug exposure, the mechanism underlying primary resistance before treatment still remain elusive. Here, we performed single-cell lineage tracing and RNA sequencing to identify sorafenib-resistant lineages in HCC, and demonstrated that high expression of S100A14 was positively associated with primary sorafenib resistance. Knocking down S100A14 rendered xenograft tumors in mice significantly more sensitive to sorafenib. Mechanistic studies indicated that S100A14 binds to glutaminase and blocks its phosphorylation at residues Y308 and S314, which in turn inhibits its ubiquitination and subsequent degradation. This stabilization of glutaminase reduces oxidative stress in HCC cells and thereby antagonizes the ability of sorafenib to induce apoptosis. Inhibiting glutaminase with telaglenastat (CB-839) significantly improved sorafenib efficacy against xenograft tumors in vivo. These results suggest that S100A14 can contribute to primary sorafenib resistance in HCC by stabilizing glutaminase. Thus, analyzing the expression of S100A14 may be useful for predicting primary sorafenib resistance, and inhibiting S100A14 or glutaminase may be effective for preventing or overcoming such resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282234 | GEO | 2025/03/02

REPOSITORIES: GEO

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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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Endogenous protein S100A14 stabilizes glutaminase to render hepatocellular carcinoma resistant to sorafenib

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