Targeting Cancer Drug-Tolerant Persister Cells in Minimal Residual Disease

Cancer cells that survive therapeutic drug pressure are a significant cause of disease relapse and progression, impeding curative cancer treatment. Drug-triggered Darwinian selection and the emergence of subclones harbouring specific mutations that confer resistance have been well documented and extensively studied. However, these genetic alterations, while important, do not fully explain clinical observations where some patients, after a drug holiday, regain sensitivity to the same treatment despite previous disease progression. This phenomenon highlights the possibility that drug resistance may not solely rely on genetic mutations but could also involve reversible, non-genetic mechanisms. Recent studies have highlighted the existence of drug-tolerant persister cells (DTPs), a subpopulation of cancer cells that can survive short-term therapeutic pressure without acquiring resistance-associated genetic alterations. These cells exhibit a temporary yet reversible tolerance to the initial treatment while also acquiring cross-tolerance to other anticancer therapies. The presence of DTPs underscores a dynamic and complex plasticity in tumours, wherein cancer cells can utilise epigenetic rewiring, metabolic reprogramming, and specific signalling pathways to transit between drug-tolerant and drug-sensitive states to adapt to environmental pressures. Furthermore, this adaptive resilience enables DTPs to act as a reservoir for the development of genetically stable resistance, resulting in cancer therapy failure and eventual relapse. In this mini-review, we examine recent evidence on DTPs to provide an overview of their characteristics, development, and survival mechanisms.