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.

Processing body dynamics drive non-genetic MEK inhibitors tolerance by fine-tuning KRAS and NRAS translation

“…For many decades, studies have pointed genetic mutations as the central mechanism of resistance acquisition to targeted therapy [20]. However, growing evidence challenges this consensus, indicating that non-genetic heterogeneity and cell plasticity actively participate in drug tolerance [21][22][23]. Recently, new profiling techniques, like FATE-seq, have been carried out to dissect the non-genetic mechanisms of resistance [24].…”

AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew

“…The presence of DTPs in the bone marrow of cancer patients after therapeutic intervention, a condition termed the minimal residual disease, indicates a high probability of cancer relapse. It has been previously hypothesized that DTP cells originate from the tumour cells residing in hybrid or mesenchymal states along the EMT/MET spectrum [ 125 , 126 ].…”

Tumor Heterogeneity and Consequences for Bladder Cancer Treatment

“…Although tolerant cells may pre-exist in the tumor, it has been shown that some cells become DTPs through EMT and phenotype plasticity following drug exposure [ 101 , 102 , 103 ].While there is currently no consensus on specific markers associated with DTPs [ 103 ], the accumulation of DTPs can occur in different tumor types by seemingly different mechanisms.…”

“…Once drug exposure was stopped, DTPs resumed growth and reacquired EGFR TKI sensitivity, suggesting a nonmutational mechanism of resistance [ 105 ]. DTPs can survive for months, allowing time for the development of new resistant clones through the acquisition of driver mutations and creating a link between nonmutational and mutational resistance mechanisms [ 103 , 106 ]. Therefore, an increased understanding of cellular plasticity and of the mechanisms surrounding the development DTPs will be key in preventing cancer drug tolerance.…”