Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells

Abstract

Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.

Keywords: adaptive resistance; cellular plasticity; collateral vulnerability; drug tolerance; stress response.

Figure 1

Cancer cells can acquire drug resistance via genetic and non-genetic adaptation mechanisms. Cancer cells initially respond to drug exposure. However, few malignant cells can survive the treatment. (A) Pre-existing clones, with specific genetic mutations, are intrinsically resistant to targeted therapy and allow for the tumor to regrow. (B) In the absence of pre-existing genetic mutations, few drug-tolerant persister cells are spared during drug treatment, and over time, these cells can give rise to tumor relapse. (C) From the pool of drug-tolerant persister cells, different genetic and non-genetic resistance mechanisms can emerge and contribute to tumor regrowth.

Figure 2

Features and vulnerabilities of drug-tolerant persister cells. Specific characteristics of drug-tolerant persister (DTP) cells are linked to the development of vulnerabilities that, in turn, can be exploited to eliminate them. Persister cells are characterized by deep transcriptional reprogramming, allowing survival in the presence of cytotoxic drugs. Transcriptional changes enable the slowdown of DTP proliferation and favor the upregulation of error-prone DNA polymerase. DTPs show altered metabolism, becoming more dependent on oxidative phosphorylation and antioxidant mechanisms. Alternative sources of nutrients can be obtained by upregulating autophagy and fatty acid oxidation. Lastly, cellular plasticity allows DTPs to evade immune-mediated clearance, and the upregulation of anti-apoptotic mechanisms protects persister cells from cytotoxic drugs.