PHARMACOLOGICAL TARGETING OF DRUG-TOLERANT PERSISTER CELLS TO OVERCOME CANCER TREATMENT RESISTANCE
DOI:
https://doi.org/10.65327/bp.v12i2.2536Keywords:
Drug-tolerant persister cells, cancer resistance, precision pharmacology, ferroptosis, residual diseaseAbstract
The presence of drug-tolerant persister (DTP) cells is a non-genetic reservoir that can be reversibly switched on after treatment with anticancers and is responsible for the residual disease, stable resistance and recurrence. In this review, the authors explore the origins of DTP cells, their mechanisms of survival, microenvironmental regulation, and the pharmacologically targeted vulnerabilities of DTP cells in the context of major cancer types and therapeutic modalities. Epigenetic reprogramming, adaptive oncogenic signalling, mitochondrial and lipid metabolic dependence, autophagy, oxidative-stress regulation, DNA repair, phenotypic plasticity and evasion of apoptosis and ferroptosis all contribute to persister survival. These adaptations provide opportunities for epigenetic inhibitors, metabolic therapies, ferroptosis inducers, apoptosis-restoring agents, pathways-directed combination treatments, and persister-specific targeted therapies. Combinations can be used upfront to avoid DTP formation, or over a period of time (sequential or intermittent) can be used to exploit the weaknesses that develop following initial therapy. Clinical translation is limited due to variability in definitions, differences in models, lack of validated biomarkers, and lack of clarity about the "when" and "how" of treatment, and about treatment toxicity. Combining single-cell and spatial profiling, liquid-biopsy monitoring and adaptive clinical trials may allow for accurate identification and interception of residual persister states. Preventing the development of permanent tolerance may make treatments more durable and decrease the likelihood of cancer recurrence.
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