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Updated: May 27, 2026
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Pharmacological induction of mitochondria-lysosome hyper-tethering elicits synthetic lethality in glioblastoma
Dongyuan Su1, Yanping Huang1, Biao Hong2
1Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro Injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China.
Abstract:
The clinical translation of synthetic lethality between cytoplasmic phospholipase A2 (cPLA2) and dipeptidyl peptidase 4 (DPP4) in glioblastoma (GBM) has been hindered by the absence of clinically applicable cPLA2 inhibitors. In this study, we demonstrate that quinacrine, a clinically available drug with cPLA2 inhibitory activity, synergizes with the DPP4 inhibitor linagliptin to exert potent anti-tumour effects. This combination synergistically depleted mitochondrial proteins, and inhibited GBM growth, significantly prolonging survival compared with temozolomide. Mechanistically, quinacrine promoted p62-dependent autophagic degradation of both cPLA2 and the mitochondrial fission protein FIS1, while linagliptin disrupted a DPP4-EGFR positive feedback loop, impairing EGFR-mediated phosphorylation of RAB7 at Ser72 and thereby stabilizing GTP-bound RAB7. These parallel inhibitions converged to enhance the frequency and duration of mitochondria-lysosome contacts, leading to massive mitochondrial degradation and bioenergetic collapse through a process termed mitochondria-lysosome hyper-tethering (MLHT). Furthermore, we established a composite transcriptional signature (DPP4-CPLA2-FIS1, DCF score) that reflects axis activity and enables metabolic stratification and therapeutic guidance for GBM. Our work not only presents a clinically feasible strategy for GBM treatment but also redefines the synthetic lethal interaction by shifting the target pair from cPLA2-DPP4 to the effector pair FIS1-RAB7, establishing hyper-activated mitochondria-lysosome tethering as a druggable anti-tumour mechanism.
Insights
Quinacrine and linagliptin synergize to treat glioblastoma (GBM) by degrading mitochondria. This novel approach, targeting mitochondria-lysosome hyper-tethering, offers a promising clinical strategy for GBM patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioblastoma (GBM) treatment is limited by lack of effective therapies.
- Synthetic lethality between cytoplasmic phospholipase A2 (cPLA2) and dipeptidyl peptidase 4 (DPP4) shows promise but lacks clinical inhibitors.
- Quinacrine and linagliptin are clinically available drugs.
Purpose of the Study:
- To investigate the anti-tumour effects of combining quinacrine (a cPLA2 inhibitor) and linagliptin (a DPP4 inhibitor) in glioblastoma.
- To elucidate the underlying molecular mechanisms of their synergistic action.
- To develop a predictive biomarker for therapeutic response.
Main Methods:
- Combination therapy with quinacrine and linagliptin in GBM models.
- Analysis of mitochondrial protein levels and autophagic degradation pathways.
- Investigation of the DPP4-EGFR feedback loop and RAB7 stabilization.
- Assessment of mitochondria-lysosome contacts and bioenergetic function.
- Development of a composite transcriptional signature (DCF score).
Main Results:
- The combination therapy potently inhibited GBM growth and prolonged survival compared to temozolomide.
- Synergistic depletion of mitochondrial proteins and induction of mitochondria-lysosome hyper-tethering (MLHT) were observed.
- Quinacrine induced p62-dependent degradation of cPLA2 and FIS1.
- Linagliptin disrupted the DPP4-EGFR loop, stabilizing GTP-bound RAB7.
- The DCF score effectively stratified patients and guided therapy.
Conclusions:
- Quinacrine and linagliptin combination therapy is a clinically feasible strategy for GBM treatment.
- The study redefines the synthetic lethal interaction, highlighting FIS1-RAB7 as key effectors.
- Hyper-activated mitochondria-lysosome tethering represents a druggable anti-tumour mechanism in GBM.
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