Abstract
Relapsed disease following first-line therapy remains one of the central problems in cancer management, including chemotherapy, radiotherapy, growth factor receptor-based targeted therapy, and immune checkpoint-based immunotherapy. Cancer cells develop therapeutic resistance through both intrinsic and extrinsic mechanisms including cellular heterogeneity, drug tolerance, bypassing alternative signaling pathways, as well as the acquisition of new genetic mutations. Reactive oxygen species (ROSs) are byproducts originated from cellular oxidative metabolism. Recent discoveries have shown that a disabled antioxidant program leads to therapeutic resistance in several types of cancers. ROSs are finely tuned by dysregulated microRNAs, and vice versa. However, mechanisms of a crosstalk between ROSs and microRNAs in regulating therapeutic resistance are not clear. Here, we summarize how the microRNA–ROS network modulates cancer therapeutic tolerance and resistance and direct new vulnerable targets against drug tolerance and resistance for future applications.
Highlights
There are many types of free radicals including oxygen- and nitrogen-based species
Succinate accumulation caused by functional loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase complex stabilizes hypoxia-inducible factor (HIF)-1α via inhibition of prolyl hydroxylase (PHD) [16]
Histologic transformation of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer to small cell lung cancer is an important mechanism of resistance to EGFR tyrosine kinase inhibitors that occurs in approximately 3–10% of EGFR mutant non-small cell lung cancers [132]
Summary
The discovery of genetic mutation on tyrosine kinase, such as EGFR mutations including exon 19 deletion (Del19) and exon 21 Leu858Arg substitution (L858R), that confer sensitivity to EGFR-targeted tyrosine kinase inhibitors in lung adenocarcinomas heralded the beginning of the era of precision medicine for lung cancer [91,92]. These findings align with previous data showing that tumor cells enter into a tolerant state when they are treated with tyrosine kinase inhibitors in lung and other cancers [100,101,102] These tolerant persister cells precede and evolve into resistant cells over time by acquiring EGFR-resistant mutations [98,99]. Functional loss of miR-21 reduces a frequency of tumor-initiating cells, consistently with decreased capacity of therapeutic resistance against EGFR tyrosine kinase inhibitors [82] (Table 1). Whether these miRNAs regulate ROSs resulting in therapeutic tolerance and resistance still needs further study. Targeting enriched tumor-initiating cells might overcome miRNA–ROS-mediated therapeutic tolerance/resistance
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