Telomerase Dysfunction Strategy Overcomes Targeted Therapy Induced Drug Tolerant Persister in Pan-cancer via SUCLG2 downregulation

The evolution of cancer cells from a drug-tolerant persister (DTP) state into stably resistant clones is a primary barrier to the long-term efficacy of targeted therapies. Through longitudinal transcriptomic profiling across melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer models, we uncover a conserved, biphasic regulation of telomerase as a fundamental driver of this process. Combining targeted therapies with telomerase inhibition (genetic or pharmacological) in melanoma and NSCLC models suppressed DTP cell formation and resistance progression in vitro and in vivo. Mechanistic dissection via RNA-seq revealed SUCLG2 as a critical downstream effector of the telomerase inhibitor 6-thio-dG; SUCLG2 knockdown phenocopied combinatorial efficacy. Complementary ATAC-seq demonstrated 6-thio-dG–induced chromatin remodelling at the SUCLG2 locus, reducing accessibility to downregulate expression and thereby impeding DTP proliferation and resistance evolution. Collectively, we establish preemptive telomerase inhibition as a vulnerability-directed strategy to ablate adaptive resistance across malignancies.