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Context dependent isoform specific PI3K inhibition confers drug resistance in hepatocellular carcinoma cells
Kubra Narci1, Deniz Cansen Kahraman1, Altay Koyas1
1Cancer System Biology Laboratory, CanSyL, Graduate School of Informatics, Middle East Technical University, 06800, Ankara, Turkey.
Background:
Targeted therapies for Primary liver cancer (HCC) is limited to the multi-kinase inhibitors, and not fully effective due to the resistance to these agents because of the heterogeneous molecular nature of HCC developed during chronic liver disease stages and cirrhosis. Although combinatorial therapy can increase the efficiency of targeted therapies through synergistic activities, isoform specific effects of the inhibitors are usually ignored. This study concentrated on PI3K/Akt/mTOR pathway and the differential combinatory bioactivities of isoform specific PI3K-α inhibitor (PIK-75) or PI3K-β inhibitor (TGX-221) with Sorafenib dependent on PTEN context.
Methods:
The bioactivities of inhibitors on PTEN adequate Huh7 and deficient Mahlavu cells were investigated with real time cell growth, cell cycle and cell migration assays. Differentially expressed genes from RNA-Seq were identified by edgeR tool. Systems level network analysis of treatment specific pathways were performed with Prize Collecting Steiner Tree (PCST) on human interactome and enriched networks were visualized with Cytoscape platform.
Results:
Our data from combinatory treatment of Sorafenib and PIK-75 and TGX-221 showed opposite effects; while PIK-75 displays synergistic effects on Huh7 cells leading to apoptotic cell death, Sorafenib with TGX-221 display antagonistic effects and significantly promotes cell growth in PTEN deficient Mahlavu cells. Signaling pathways were reconstructed and analyzed in-depth from RNA-Seq data to understand mechanism of differential synergistic or antagonistic effects of PI3K-α (PIK-75) and PI3K-β (TGX-221) inhibitors with Sorafenib. PCST allowed as to identify AOX1 and AGER as targets in PI3K/Akt/mTOR pathway for this combinatory effect. The siRNA knockdown of AOX1 and AGER significantly reduced cell proliferation in HCC cells.
Conclusions:
Simultaneously constructed and analyzed differentially expressed cellular networks presented in this study, revealed distinct consequences of isoform specific PI3K inhibition in PTEN adequate and deficient liver cancer cells. We demonstrated the importance of context dependent and isoform specific PI3K/Akt/mTOR signaling inhibition in drug resistance during combination therapies. ( https://github.com/cansyl/Isoform-spesific-PI3K-inhibitor-analysis ).
Insights
Targeted therapies for liver cancer (HCC) show varied efficacy. This study reveals that combining PI3K isoform-specific inhibitors with Sorafenib yields different outcomes based on PTEN status, impacting treatment effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Primary liver cancer (HCC) treatment faces challenges due to drug resistance stemming from molecular heterogeneity.
- Current multi-kinase inhibitors for HCC are not fully effective, and combinatorial therapies often overlook isoform-specific inhibitor effects.
- The PI3K/Akt/mTOR pathway is a key target, but its modulation requires understanding isoform-specific actions in combination therapy.
Purpose of the Study:
- To investigate the differential combinatory bioactivities of PI3K-α (PIK-75) and PI3K-β (TGX-221) inhibitors with Sorafenib.
- To elucidate the role of PTEN context in mediating the effects of these combined targeted therapies.
- To understand the molecular mechanisms underlying synergistic or antagonistic responses in HCC cells.
Main Methods:
- Cell-based assays (growth, cell cycle, migration) were used to assess inhibitor effects on PTEN-adequate (Huh7) and PTEN-deficient (Mahlavu) HCC cells.
- RNA-Seq and edgeR were employed for differential gene expression analysis.
- Systems-level network analysis using Prize Collecting Steiner Tree (PCST) and visualization with Cytoscape identified key pathways and targets.
Main Results:
- Combinations of Sorafenib with PIK-75 showed synergistic effects (apoptosis) in Huh7 cells, while Sorafenib with TGX-221 exhibited antagonistic effects (promoting growth) in Mahlavu cells.
- RNA-Seq and network analysis identified AOX1 and AGER as crucial targets within the PI3K/Akt/mTOR pathway mediating these differential effects.
- siRNA knockdown of AOX1 and AGER significantly inhibited HCC cell proliferation.
Conclusions:
- Isoform-specific PI3K inhibition has distinct consequences in PTEN-adequate versus PTEN-deficient liver cancer cells.
- Context-dependent and isoform-specific targeting of the PI3K/Akt/mTOR pathway is crucial for overcoming drug resistance in combination therapies for HCC.
- This study highlights the importance of considering PTEN status and PI3K isoform activity for optimizing targeted combination treatments in liver cancer.
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