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Resistance to chemotherapy: short-term drug tolerance and stem cell-like subpopulations.

ABSTRACT: Personalized medicine in cancer treatment has been a major goal for decades. Recently, the development of several therapies that specifically target key genetic alterations in different malignancies has dramatically improved patient outcome and brought the goal of personalized medicine closer to practicality. Despite the improved specificity of these treatment options, resistance to targeted therapy is common and remains a major obstacle to long-term management of a patient's disease. Often patient relapse is a result of the positive selection of cells with certain genetic alterations that result in a bypass of the therapeutic intervention. Once this occurs, patient relapse is inevitable and further treatment options are limited. The time to relapse is often quite rapid indicating that cancer cells may be primed for adapting to cytotoxic stimuli. Recently, it has been suggested that small subpopulations of cells allow resistance to occur more rapidly. It is thought that these cells are capable of surviving strong apoptotic stimuli until more permanent mechanisms of long-term resistance are developed. In order to decrease the rate of patient relapse, more studies are required in order to identify these subpopulations of cells, understand the mechanisms underlying their drug tolerance, and develop strategies to prevent them from evading treatment.

SUBMITTER: Basile KJ

PROVIDER: S-EPMC6874398 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Resistance to chemotherapy: short-term drug tolerance and stem cell-like subpopulations.

Basile Kevin J KJ Aplin Andrew E AE

Advances in pharmacology (San Diego, Calif.) 20120101

Personalized medicine in cancer treatment has been a major goal for decades. Recently, the development of several therapies that specifically target key genetic alterations in different malignancies has dramatically improved patient outcome and brought the goal of personalized medicine closer to practicality. Despite the improved specificity of these treatment options, resistance to targeted therapy is common and remains a major obstacle to long-term management of a patient's disease. Often pati ...[more]

PMID: 22959030

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Project description:Initial responses to tuberculosis treatment are poor predictors of final therapeutic outcomes in drug-susceptible disease, suggesting that treatment success depends on features that are hidden within a small minority of the overall infecting Mycobacterium tuberculosis population. We developed a multitranswell robotic system to perform numerous parallel cultures of genetically barcoded M. tuberculosis exposed to steady-state concentrations of rifampicin to uncover these difficult-to-eliminate minority populations. We found that tolerance emerged repeatedly from at least two subpopulations of barcoded cells, namely, one that could not grow on solid agar media and a second that could form colonies, but whose kill curves diverged from the general bacterial population within 4 and 16 days of drug exposure, respectively. These tolerant subpopulations reproducibly passed through a phase characterized by multiple unfixed resistance mutations followed by emergent drug resistance in some cultures. Barcodes associated with drug resistance identified an especially privileged subpopulation that was rarely eliminated despite 20 days of drug treatment even in cultures that did not contain any drug-resistant mutants. The association of this evolutionary scenario with a defined subset of barcodes across multiple independent cultures suggested a transiently heritable phenotype, and indeed, glpK phase variation mutants were associated with up to 16% of the resistant cultures. Drug tolerance and resistance were eliminated in a ΔruvA mutant, consistent with the importance of bacterial stress responses. This work provides a window into the origin and dynamics of bacterial drug-tolerant subpopulations whose elimination may be critical for developing rapid and resistance-free cures. IMPORTANCE Tuberculosis is unusual among bacterial diseases in that treatments which can rapidly resolve symptoms do not predictably lead to a durable cure unless treatment is continued for months after all clinical and microbiological signs of disease have been eradicated. Using a novel steady-state antibiotic exposure system combined with chromosomal barcoding, we identified small hidden Mycobacterium tuberculosis subpopulations that repeatedly enter a state of drug tolerance with a predisposition to develop fixed drug resistance after first developing a cloud of unfixed resistance mutations. The existence of these difficult-to-eradicate subpopulations may explain the need for extended treatment regimen for tuberculosis. Their identification provides opportunities to test genetic and therapeutic approaches that may result in shorter and more effective TB treatments.

Dataset Information

Resistance to chemotherapy: short-term drug tolerance and stem cell-like subpopulations.

Publications

Resistance to chemotherapy: short-term drug tolerance and stem cell-like subpopulations.

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