A telomerase and SUCLG2 pathway may help drug-resistant persistent cells survive

Transcriptomic profiling revealed a conserved biphasic telomerase regulation during drug-tolerant persister evolution in several cancer models.

• Drug-tolerant persister cells are associated with the evolution of resistant clones, posing challenges to targeted therapies.
• The agent 6-thio-dG, which induces telomere dysfunction, has been shown to effectively suppress drug-tolerant persister outgrowth and resistance both in vitro and in vivo.
• 6-thio-dG triggers chromatin changes that limit access to the SUCLG2 gene, resulting in reduced expression of a key mitochondrial enzyme.
• Downregulation of SUCLG2 disrupts the metabolic stability necessary for the survival of drug-tolerant persister cells.
• Combining 6-thio-dG with targeted therapies demonstrates a coordinated suppression of mitochondrial metabolism, telomere maintenance, and transcriptional programs related to persister cells.

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