Drug-tolerant persister cells: the deadly survivors in hematological malignancies

Although the prognosis of patients with hematologic cancers has improved significantly owing to the advance of radiotherapy, chemotherapy, targeted therapies, immunotherapies, and hematopoietic stem cell transplantation therapy, disease relapse and refractory are still very prevalent and remain the major obstacles for long-term patient survival. Recent evidence suggests that drug-tolerant persister (DTP) cells are considered to be the cellular reservoir for tumor relapses and drug resistance formation. DTP cells refer to tumor cells that are acquired tolerance to anticancer drugs during exposure. Distinct from genetic mutations which cause stable drug-resistance, drug-tolerance in DTP cells is reversible which is primarily mediated by non-genetic alterations including changes in epigenetic modification, metabolic reprogramming, and/or transcriptional regulation. However, under prolonged or repeat drug-exposure, DTP cells acquire mutations in genes that are required for drug-treatment response and become stable drug-resistance. Targeting stable drug-resistant cell therapy is very challenge which needs novel drugs. Thus, targeted DTP cells therapy is particularly interesting which only needs to inhibit the essential adaptive pathways to prevent DTP cells formation or restore drug-sensitivity to DTP cells. During the past 15 years, significant efforts have been made to understand the mechanisms that drive the generation of DTP cells and define unique vulnerabilities that can be exploited for targeting DTP cells therapies. Combination of drug with adaptive pathway inhibitors has been attempted to prevent recurrence and refractory for durable treatment efficacy. Here, we review the advances of DTP cells research in hematologic cancers and summarize the phenotypic and functional characterizations of DTP cells defined in different research models. By deliberating the mechanisms of DTP cells generation and evolution, we discuss the potential therapeutic strategies of targeting DTP cells for more an effective treatment of hematological malignancies.