Drug-tolerant persister cells

First described by Sharma et al. (2010) in EGFR-mutant lung cancer cells surviving erlotinib, persisters are a reversible, largely non-genetic state resembling bacterial persistence and embryonic diapause: slow-cycling, with chromatin changes (KDM5A-dependent histone demethylation, H3K27me3 gain), activation of IGF1R, YAP/TAZ, NF-κB, Notch and AXL, autophagy, altered metabolism (reliance on fatty acid oxidation, low glutathione), reduced apoptotic priming, upregulated ABC transporters, and a mesenchymal-like, ALDH-high phenotype. Their lipid metabolism creates dependence on GPX4, so ferroptosis inducers kill them selectively in models. During persistence, downregulated repair and APOBEC activity increase mutagenesis, so genuine resistance mutations (EGFR T790M, C797S) often arise from persisters ('bet hedging' then 'commitment'). MRD detected by ctDNA after targeted therapy or in adjuvant settings partly reflects this population; senescence-like persisters share SASP features. Strategies: drug holidays and intermittent dosing to prevent commitment, GPX4/ferroptosis inducers, BCL-XL/MCL-1 inhibitors to remove the survival buffer, KDM5 or EZH2 inhibitors to block the epigenetic switch, and upfront combinations that hit the persister programme (osimertinib + chemotherapy in FLAURA2, + amivantamab in MARIPOSA).