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

By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

Automated summary

By emphasizing drug efficacy and inhibiting resistance mechanisms, combinatorial therapies have emerged as a key approach in complex disease treatment, particularly cancer. Through high-throughput drug screens, researchers identified metabolic vulnerabilities in tumor cells, leading to a combinatorial response that induced cell death through enhanced pyrimidine catabolism and reduced pyrimidine synthesis. This approach sensitized human organoid cultures to standard chemotherapy and could potentially be implemented into established treatment regimens, with the added benefit of drug repurposing.