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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
Targeting EIF4A1 is effective against human intrahepatic cholangiocarcinoma
Wunan Mi1, Antonio Cigliano2, Grazia Galleri3
1Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Background & Aims:
Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary liver tumor, characterized by clinical aggressiveness, dismal outcome, and limited therapeutic options. Thus, innovative treatments are urgently required to improve the prognosis of patients with iCCA.
Methods:
In this study, we determined the pathogenetic and therapeutic role of eukaryotic initiation factor 4A1 (EIF4A1), a subunit of the eIF4F complex involved in translation initiation, in human iCCA.
Results:
Preinvasive (n = 12), invasive (n = 162), and metastatic (n = 14) iCCA lesions exhibited ubiquitous eIF4A1 upregulation. In addition, eIF4A1 mRNA levels from 42 specimens showed a significantly higher expression in iCCA samples compared with non-tumorous tissues (p <0.0001) or large duct-type lesions (p = 0.020). Furthermore, eIF4A1 expression was inversely associated with patient prognosis (p <0.001). Moreover, zotatifin, an eIF4A1-specific inhibitor in clinical trials, significantly reduced the growth of iCCA cell lines, iCCA cancer-associated fibroblasts (CAFs), and patient-derived tumor organoids. At the metabolic level, zotatifin decreased glycolysis of iCCA cells without affecting mitochondrial respiration. Moreover, the Bcl-xl inhibitors A-1155463 and DT2216 profoundly augmented apoptotic cell death when administered in association with zotatifin.
Conclusions:
The data highlight eIF4A1 as a potential target for treating iCCA. Combined inhibition of eIF4A1 and Bcl-xl could offer an effective therapeutic strategy against this deadly disease.
Impact And Implications:
Dysregulation of the translational machinery is a hallmark of cancer, often linked to tumor progression and poor prognosis. This study underscores the potential of zotatifin, a specific inhibitor of EIF4A1 (an essential component of translation initiation) to inhibit the growth of iCCA cells. In addition, zotatifin demonstrated a synergistic effect when used in combination with the Bcl-xl inhibitors A-1155463 and DT2216, significantly enhancing cell apoptosis. Although this investigation did not include an in vivo model, its results, derived from iCCA cell lines, patient-derived organoids, and CAFs, are consistent with the encouraging preliminary results of zotatifin in clinical trials. From a clinical standpoint, these results suggest that zotatifin improves patient outcomes by inhibiting iCCA growth and reducing tumor aggressiveness. Furthermore, combining zotatifin with other drugs could represent a promising therapeutic strategy for targeting iCCA.
Insights
Eukaryotic initiation factor 4A1 (EIF4A1) is upregulated in intrahepatic cholangiocarcinoma (iCCA) and linked to poor prognosis. Targeting EIF4A1 with zotatifin, especially combined with Bcl-xl inhibitors, shows promise for treating this aggressive liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Translational Medicine
Background:
- Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver cancer with limited treatment options.
- Upregulation of translation initiation factors is implicated in cancer progression and poor outcomes.
- Innovative therapeutic strategies are crucial for improving iCCA patient prognosis.
Purpose of the Study:
- To investigate the role of eukaryotic initiation factor 4A1 (EIF4A1) in the pathogenesis of human iCCA.
- To evaluate the therapeutic potential of EIF4A1 inhibition in iCCA models.
- To explore combination therapies involving EIF4A1 inhibition for iCCA treatment.
Main Methods:
- Analysis of EIF4A1 expression in preinvasive, invasive, and metastatic iCCA lesions.
- Correlation of EIF4A1 mRNA levels with iCCA patient prognosis.
- Assessment of the effect of zotatifin (an EIF4A1 inhibitor) on iCCA cell lines, cancer-associated fibroblasts (CAFs), and patient-derived organoids.
- Evaluation of zotatifin's impact on cellular metabolism (glycolysis and mitochondrial respiration).
- Investigation of synergistic effects between zotatifin and Bcl-xl inhibitors (A-1155463, DT2216) on iCCA cell apoptosis.
Main Results:
- EIF4A1 was ubiquitously upregulated across all stages of iCCA and significantly higher in iCCA tissues compared to non-tumorous tissues.
- Higher EIF4A1 expression was inversely associated with a poorer patient prognosis.
- Zotatifin treatment significantly inhibited the growth of iCCA cells, CAFs, and organoids, while decreasing glycolysis.
- Combined treatment with zotatifin and Bcl-xl inhibitors profoundly increased apoptotic cell death.
Conclusions:
- EIF4A1 is a potential therapeutic target for intrahepatic cholangiocarcinoma.
- Combined inhibition of EIF4A1 and Bcl-xl represents a promising therapeutic strategy for iCCA.
- Zotatifin's efficacy in preclinical models supports its clinical investigation for iCCA treatment.
