A telomerase-SUCLG2 signaling axis drives drug resistance by protecting persister cells

The evolution of drug-tolerant persister (DTP) cells into resistant clones remains a major obstacle to targeted therapies. Transcriptomic profiling across melanoma (A375, SK-MEL-28), non-small cell lung cancer (NSCLC; HCC827, PC-9), and colorectal cancer (CRC; SW480) models revealed a conserved biphasic telomerase regulation during DTP evolution. Combining targeted therapies with the telomere-dysfunction agent 6-thio-dG effectively suppressed DTP outgrowth and resistance in vitro and in vivo. Mechanistically, 6-thio-dG induces chromatin remodeling, reducing SUCLG2 locus accessibility and downregulating this mitochondrial enzyme to disrupt DTP metabolic stability. Consistently, SUCLG2 knockdown recapitulated these therapeutic effects. Furthermore, in vivo RNAseq of HCC827 xenografts confirmed the combination coordinately suppresses mitochondrial metabolism, telomere maintenance, and persister programs. Collectively, preemptively combining 6-thio-dG with targeted therapies is a potent strategy to disrupt DTP evolution and overcome adaptive resistance across diverse malignancies.