Abstract
Simple SummaryAcquired resistance to molecularly targeted therapies remains a major challenge in the treatment of cancer. It has been hypothesized that drug-tolerant (or “persister”) cells without bona fide resistance mechanisms may survive initial drug treatment and undergo further evolution over time to acquire resistance mechanisms leading to cancer relapse. In this review, we will discuss insights into mechanisms and vulnerabilities of these cells revealed by recent in vitro, in vivo, and clinical studies.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.
Highlights
Over the past decades, we have seen the development and evolution of molecularly targeted therapies for treating cancer
Examples of these targeted cancer therapeutics that have markedly improved patient survival are tyrosine kinase inhibitors (TKIs) that block or suppress the activity of oncogenic driver receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase (EML4-ALK) in non-small cell lung cancer (NSCLC), as well as mitogen-activated protein kinase (MAPK) pathway-directed agents against mutant B-Raf (BRAF) in melanoma and other solid tumors [1,2,3,4,5,6,7]
We provide an overview of the characteristics of drug-tolerant persister cells in cancer, how they arise, and the mechanisms these cells utilize to evade targeted therapy
Summary
We have seen the development and evolution of molecularly targeted therapies for treating cancer. PC9 single-cell cultures that did not harbor pre-existing EGFRT790M cells eventually gave rise to EGFRT790M or other genomic mechanisms of resistance when treated with EGFR inhibitor continuously for extended periods of time, demonstrating de novo evolution of drug resistance mechanisms from persisters These findings were corroborated with transcriptional profiling showing that the late-resistant clones retained features of the drug-tolerant state, while the early-resistant clones showed transcriptional profiles more similar to that of the parental cells. In contrast to drug resistance, drug-tolerant persister cells are “tolerant” to the drug in the sense that the drug does not induce cell death, but still exerts a suppressive effect In the clinic, this corresponds to the period of time after maximal tumor regression but before quantifiable tumor growth, despite continued therapy (Figure 3C). For an excellent review on cancer stem cells and anticancer drug resistance, we refer the reader to an excellent review by Shibue and Weinberg [59]
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