Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer

Abstract

Drug resistance is perhaps the greatest challenge in improving outcomes for cancer patients undergoing treatment with targeted therapies. It is becoming clear that “persisters,” a subpopulation of drug-tolerant cells found in cancer populations, play a critical role in the development of drug resistance. Persisters are able to maintain viability under therapy but are typically slow cycling or dormant. These cells do not harbor classic drug resistance driver alterations, and their partial resistance phenotype is transient and reversible upon removal of the drug. In the clinic, the persister state most closely corresponds to minimal residual disease from which relapse can occur if treatment is discontinued or if acquired drug resistance develops in response to continuous therapy. Thus, eliminating persister cells will be crucial to improve outcomes for cancer patients. Using lung cancer targeted therapies as a primary paradigm, this review will give an overview of the characteristics of drug-tolerant persister cells, mechanisms associated with drug tolerance, and potential therapeutic opportunities to target this persister cell population in tumors.

Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer

“…Our findings contribute to the understanding of the aetiology and genetic context of quiescence in cancer. This is particularly relevant to identifying new anti-proliferative targets, but also for the detection and eradication of drug tolerant persister cells, which have been frequently, although not always, observed to be driven by slow cycling or entirely quiescent 7,8 . Importantly, the state of cancer quiescence that we have studied here is distinct from that of disseminated tumour cells causing clinical dormancy and cancer relapse, often after many years from the treatment of the primary tumour 6,94 .…”

“…It has been proposed that this state enables cells to become resistant to anti-cancer compounds that target actively dividing cells, such as chemotherapy [3][4][5] . Moreover, a drug-tolerant 'persister' cell state represented by slow cycling or entirely quiescent cells [6][7][8][9] has been observed in a variety of pre-existing or acquired resistance scenarios, also in the context of targeted therapies 10,11 . As neoplastic cells evolve, quiescence can also be employed as a mechanism to facilitate immune evasion 12,13 or adaptation to new environmental niches during metastatic seeding 14,15 .…”

Challenges in the Use of Targeted Therapies in Non–Small Cell Lung Cancer

“…These cells are thought to be different from cancer stem cells (CSCs). Persister cells tend to lack classic drug resistance driver alterations and their resistant phenotype could be transient and reversible upon removal of the treatment drug [ 98 ]. In contrast, CSCs are cells within a tumor with the ability to self-renew and generate heterogenous lineages of cancer cells [ 99 ].…”

The Role of Tumor Stem Cell Exosomes in Cancer Invasion and Metastasis

“…The drug-resistant phenotype is temporary and can be reversed after drug removal. Tumors can relapse if treatment is stopped or acquired drug resistance is caused by continued treatment ( 100 ). CSCs are important factors in tumor drug resistance.…”