Drug-tolerant persister cancer cells

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Drug resistance continues to be a major bottleneck of curing patients with cancer.Two primary intracellular factors contribute to emergence of drug resistance in treatment-naïve cancer cells, which are a population of malignant cells not receiving any therapy before.One is that genetic mutations occur in key cancer-addicted genes, such as T790M in epidermal growth factor receptor (EGFR), are a critical mechanism underlying some therapeutic resistance, thus boosting the development and usage of targeted inhibitors to benefit patients with cancer.In addition, non-genetic factors, including aberrant epigenetic/metabolic machinery and/or reprogrammed transcription profile, probably play more important roles in drug resistance in cancer cells. 1 Upon receiving treatment with osimertinib, a subset of EGFR-mutated lung cancer cells acquired resistance to osimertinib through mammalian SWI/SNF complexmediated alterations in chromatin accessibility to sustain low cellular ROS level and hyperproliferation, but no new mutations occurred in EGFR. 2 Recently, researchers observed that a small group of cancer cells survived the treatment with lethal dose of chemotherapeutic or targeted drugs, and re-entered cycling phase and prospered after drug withdrawal.3 Furthermore, these flourished cell populations remained sensitive to originally administrated drugs and no additional genetic mutations in critical resistance-related genes occurred, whereby these cells are named after drug-tolerant persister cancer (DTPC) cells.3 Notably, a case report showed that DTPC cells were responsible for relapse in one patient with lung adenocarcinoma (LUAD), who had received gefitinib, thus highlighting significance of drug tolerance in clinical treatment and entailing a deeper understanding of DTPC cells and identification of therapeutic vulnerabilities.4 Whereas as of yet there is no consensus in oncology community about the definition of drug tolerance in cancer cells, we want to emphasize that plasticity is its core property ( Fig. 1 ).In contrast, drug resistance is usually a phenotype that cancer cells become stably non-responsive to drugs, at least compared with DTPC cells.Additionally, since drug tolerance is highly plastic, it is plausible to observe that this population reverses to originally "drug-sensitive " state or drug-resistant populations develop from within.Therefore, this Perspective will describe the characteristics of DTPC cells and underscore their plastic trait.

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