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NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer
Josefina Doffo1, Stefanos A Bamopoulos1, Hazal Köse1
1Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
Abstract:
Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The proapoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential of NOXA, we performed an unbiased drug screening experiment. In NOXA-deficient isogenic cellular models, we identified an inhibitor of the transcription factor heterodimer CBFβ/RUNX1. By genetic gain and loss of function experiments, we validated that the mode of action depends on RUNX1 and NOXA. Of note is that RUNX1 expression is significantly higher in PDACs compared to normal pancreas. We show that pharmacological RUNX1 inhibition significantly blocks tumor growth in vivo and in primary patient-derived PDAC organoids. Through genome-wide analysis, we detected that RUNX1-loss reshapes the epigenetic landscape, which gains H3K27ac enrichment at the NOXA promoter. Our study demonstrates a previously unknown mechanism of NOXA-dependent cell death, which can be triggered pharmaceutically. Therefore, our data show a way to target a therapy-resistant PDAC, an unmet clinical need.
Insights
Researchers identified a drug targeting CBFβ/RUNX1 to overcome pancreatic cancer resistance. This approach leverages the NOXA protein to induce cancer cell death, offering a new strategy for treating therapy-resistant pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Drug resistance in pancreatic ductal adenocarcinoma (PDAC) is a significant clinical challenge.
- Evasion of apoptosis (programmed cell death) is a key mechanism driving treatment resistance.
- The pro-apoptotic protein NOXA is associated with aggressive PDAC subtypes.
Purpose of the Study:
- To identify novel therapeutic agents that can restore NOXA's cell death-inducing capabilities.
- To investigate the role of the CBFβ/RUNX1 transcription factor in NOXA-mediated apoptosis.
- To explore new strategies for targeting therapy-resistant PDAC.
Main Methods:
- Unbiased drug screening in NOXA-deficient cellular models.
- Genetic gain and loss of function experiments to validate drug targets.
- In vivo studies using mouse models and ex vivo analysis of patient-derived organoids.
- Genome-wide analysis to investigate epigenetic changes.
Main Results:
- An inhibitor of the CBFβ/RUNX1 transcription factor heterodimer was identified.
- The drug's efficacy was dependent on RUNX1 and NOXA expression.
- RUNX1 is upregulated in PDAC compared to normal pancreas.
- Pharmacological inhibition of RUNX1 suppressed tumor growth in vivo and in PDAC organoids.
- RUNX1 loss altered the epigenetic landscape, increasing H3K27ac enrichment at the NOXA promoter.
Conclusions:
- A novel mechanism of NOXA-dependent cell death, targetable by pharmacological RUNX1 inhibition, was discovered.
- This approach offers a potential therapeutic strategy for overcoming treatment resistance in PDAC.
- The findings address a critical unmet need in targeting aggressive and therapy-resistant pancreatic cancer.
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