Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Combinatorial therapies are crucial for overcoming drug resistance in cancer.
• Identifying synergistic drug combinations targeting metabolic vulnerabilities is a key strategy.

Purpose of the Study:

• To uncover novel drug combinations that induce synergistic cancer cell death.
• To elucidate the molecular mechanisms underlying the observed cell death.
• To evaluate the potential of these combinations in sensitizing tumors to standard chemotherapy.

Main Methods:

• High-throughput drug screening to identify synergistic combinations.
• Transcriptome and metabolome analyses to characterize molecular responses.
• Utilizing human organoid cultures to assess drug efficacy in a clinical context.

Main Results:

• Domperidone and TCAs combined with NEN induced cancer cell death via integrated stress response and CLEAR network activation.
• The combination therapy led to enhanced pyrimidine catabolism and reduced synthesis, driven by CHOP and TFE3.
• Drug combinations sensitized human organoid cultures to paclitaxel.

Conclusions:

• Repurposed drugs like domperidone and TCAs can synergize with NEN to induce cancer cell death.
• This combinatorial approach targets pyrimidine metabolism and activates key transcription factors.
• The findings support the clinical implementation of these drug combinations to enhance existing cancer treatment regimens.