Z Gastroenterol 2022; 60(01): e38
DOI: 10.1055/s-0041-1740775
Abstracts | GASL

Apoptosis sensitivity of hepatocellular carcinoma to sorafenib-based treatment combinations depends on the expression pattern of BH3-only proteins

Authors

  • Katharina John

    1   Hannover Medical School

  • Stephanie Busche

    1   Hannover Medical School

  • Franziska Wandrer

    1   Hannover Medical School

  • Heiner Wedemeyer

    1   Hannover Medical School

  • Klaus Schulze-Osthoff

    2   University of Tuebingen

  • Heike Bantel

    1   Hannover Medical School
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    Background Anti-angiogenic immune checkpoint inhibitor-based combination therapy is currently used for treatment of progressed HCC, but improves survival only in a subset of patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether sorafenib response could be enhanced by the combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively.

    Methods Cell death and apoptosis were assessed by crystal-violet staining and a luminometric caspase assay. Expression of apoptosis regulators was determined by RT-PCR and Western blot analyses. In addition, siRNA-mediated knockdown experiments were performed.

    Results We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. NOXA-knockdown in HCC cells significantly impaired cell death induction by sorafenib and TRAIL. Sorafenib cytotoxicity could, however, not be enhanced by ABT-737 in the absence of BIM, even when NOXA was strongly expressed.

    Conclusion BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.


     

    Publication History

    Article published online:
    26 January 2022

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