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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment
Stephanie Busche1, Katharina John1, Franziska Wandrer1
1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Abstract:
Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC 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 the sorafenib response could be enhanced by 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. 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. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that 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.
Insights
Hepatocellular carcinoma (HCC) treatment response to sorafenib combinations depends on BH3-only proteins like NOXA and BIM. Profiling these proteins may guide patient selection for targeted HCC therapies.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Cancer biology
- Molecular targeted therapy
Background:
- Hepatocellular carcinoma (HCC) poses a significant global health challenge with limited effective treatments.
- Current therapies like tyrosine kinase inhibitors (TKIs) offer modest efficacy in advanced HCC.
- Combination therapies are being explored, but patient response remains variable.
Purpose of the Study:
- To investigate if combining sorafenib with pro-apoptotic agents (TRAIL or ABT-737) can enhance treatment efficacy in HCC.
- To determine the role of specific BH3-only proteins (NOXA, BIM) in mediating HCC cell death in response to these combinations.
- To explore the potential of BH3-only protein profiling for patient stratification in HCC therapy.
Main Methods:
- Utilized diverse HCC cell lines and patient-derived HCC tissues to model tumor heterogeneity.
- Assessed the impact of combining sorafenib with TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737 on HCC cell death.
- Analyzed the expression levels of BH3-only proteins (NOXA, BIM) and correlated them with treatment response.
Main Results:
- Both TRAIL and ABT-737 enhanced sorafenib-induced cell death, but efficacy was dependent on BH3-only protein expression.
- TRAIL's efficacy was restricted to NOXA-expressing HCC cells.
- ABT-737 showed efficacy in NOXA-deficient cells but required BIM for optimal sensitization, even with NOXA present. TRAIL combined with sorafenib sensitized BIM-deficient HCC cells when NOXA was present.
- HCC tissues sensitive to sorafenib and TRAIL combination therapy exhibited higher NOXA expression.
Conclusions:
- BH3-only protein expression (NOXA and BIM) is a critical determinant of HCC response to sorafenib-based combination therapies.
- Targeting apoptosis pathways with agents like TRAIL and ABT-737 can overcome resistance mechanisms in HCC.
- Individual BH3-only protein profiling could enable personalized treatment strategies for HCC patients, improving therapeutic outcomes.
