Biological mechanisms supporting drug-tolerant persister survival during therapy.
| Adaptive survival mechanism | Cellular processes involved | Key signaling pathways | Experimental evidence | Therapeutic targeting strategies |
|---|---|---|---|---|
| Oxidative stress adaptation | Upregulation of antioxidant defenses allowing tumor cells to tolerate therapy-induced reactive oxygen species and oxidative damage | NRF2 signaling, glutathione metabolism, redox homeostasis regulators [90, 92] | Observed in drug-tolerant persister populations in melanoma, lung cancer, and colorectal cancer models [93, 94] | Targeting redox balance using reactive oxygen species (ROS)-inducing agents or inhibitors of antioxidant pathways |
| UPR | Activation of proteostasis mechanisms that restore endoplasmic reticulum function and prevent accumulation of misfolded proteins under treatment stress | Protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2 alpha (eIF2α) pathway, activating transcription factor 4 (ATF4) signaling, inositol-requiring enzyme 1 (IRE1)-X-box binding protein 1 (XBP1) pathway [91, 95] | Therapy-induced proteotoxic stress and UPR activation reported in multiple targeted therapy models [91, 95] | Inhibition of ER stress response pathways or proteostasis regulators |
| Autophagy activation | Recycling of intracellular components to sustain energy production and remove damaged organelles during therapeutic stress | AMPK signaling, mTOR suppression, autophagy initiation complexes [84, 96] | Increased autophagy activity documented in persister cells following chemotherapy and targeted therapy [84, 96] | Autophagy inhibitors combined with targeted therapy or chemotherapy |
| Metabolic rewiring | Adaptive metabolic reprogramming enabling tumor cells to maintain energy production under therapy-induced metabolic stress | AMPK signaling, mitochondrial stress pathways, altered glucose and glutamine metabolism [68, 97] | Therapy-induced metabolic dependencies observed in targeted therapy-resistant tumor models [90, 91] | Targeting metabolic dependencies such as mitochondrial metabolism or nutrient utilization pathways |
| Adaptive signaling rewiring | Activation of compensatory signaling pathways that restore survival signaling after inhibition of oncogenic drivers | Receptor tyrosine kinase activation, PI3K-AKT signaling, MAPK pathway reactivation [87, 98] | Observed in EGFR-mutant lung cancer, BRAF-mutant melanoma, and other targeted therapy models [87, 88] | Sequential or combination therapies targeting compensatory pathways |
| Chromatin remodeling and epigenetic adaptation | Epigenetic reprogramming enabling reversible drug-tolerant states through transcriptional reorganization | Histone modification enzymes, chromatin remodeling complexes, enhancer reprogramming [68, 99] | Chromatin remodeling associated with reversible drug-tolerant persister states across multiple tumor models [68, 99] | Targeting epigenetic regulators such as histone modifiers or chromatin remodeling complexes |
AMPK: AMP-activated protein kinase; BRAF: B-Raf proto-oncogene; EGFR: epidermal growth factor receptor; NRF2: nuclear factor erythroid 2-related factor 2; MAPK: mitogen-activated protein kinase; PI3K-AKT: phosphoinositide 3-kinase-protein kinase B; UPR: unfolded protein response.
During the preparation of this work, the authors used OpenAI image-generation tools to assist with the initial preparation of conceptual figure drafts. After utilizing the tool, the authors reviewed, revised, and finalized the figures as necessary and take full responsibility for the final content of the publication.
OAAE: Investigation, Writing—original draft. MMN: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Supervision. Both authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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