Drug-Tolerant Persister Cells in Cancer Therapy Resistance

One of the current stumbling blocks in our fight against cancer is the development of acquired resistance to therapy, which is attrib-utable to approximately 90% of cancer-related deaths. Undercutting this process during treatment could significantly improve cancer management. In many cases, drug resistance is mediated by a drug-tolerant persister (DTP) cell subpopulation present in tumors, often referred to as persister cells. This review provides a summary of currently known persister cell subpopulations and approaches to target them. A specific DTP cell subpopulation with elevated levels of aldehyde dehydrogenase (ALDH) activity has stem cell-like characteristics and a high level of plasticity, enabling them to switch rapidly between high and low ALDH activity. Further studies are required to fully elucidate the functions of ALDH-high DTP cells, how they withstand drug concentrations that kill other cells, and how they rapidly adapt under levels of high cellular stress and eventually lead to more aggressive, recurrent, and drug-resistant cancer. Furthermore, this review addresses the processes used by the ALDH-high persister cell subpopulation to enable cancer progres-sion, the ALDH isoforms important in these processes, interactions of ALDH-high DTPs with the tumor microenvironment, and approaches to therapeutically modulate this subpopulation in order to more effectively manage cancer.

Automated summary

One of the challenges in cancer treatment is the development of acquired resistance to therapy, which is responsible for a large percentage of cancer-related deaths. This review focuses on persister cells, a subpopulation of drug-tolerant cells in tumors, and discusses approaches to target them. The review highlights the characteristics of a specific persister cell subpopulation with high levels of aldehyde dehydrogenase (ALDH) activity and their role in drug resistance and cancer progression. The interactions between ALDH-high persister cells and the tumor microenvironment are also explored. Therapeutic modulation of this subpopulation is proposed as a strategy for more effective cancer management.