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Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance to targeted therapy remains a major obstacle. Epithelial-mesenchymal transition (EMT) has been identified as a key resistance mechanism in NSCLC. Here, we investigated the mechanistic role of key EMT-regulating small non-coding microRNAs (miRNAs) in sublines of the NSCLC cell line HCC4006 adapted to afatinib, erlotinib, gefitinib, or osimertinib. The most differentially expressed miRNAs derived from extracellular vesicles were associated with EMT, and their predicted target ZEB1 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting ZEB1, restoring CDH1 expression, and inhibiting migration in erlotinib-resistant cells. Gene expression of EMT-markers, transcription factors, and miRNAs were correlated during stepwise osimertinib adaptation of HCC4006 cells. Temporally relieving cells of osimertinib reversed transition trends, suggesting that the implementation of treatment pauses could provide prolonged benefits for patients. Our results provide new insights into the contribution of miRNAs to drug-resistant NSCLC harboring EGFR-activating mutations and highlight their role as potential biomarkers and therapeutic targets.
Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.
Within the last decades cancer treatment improved by the availability of more specifically
acting drugs that address molecular target structures in cancer cells. However, those target-sensitive
drugs suffer from ongoing resistances resulting from mutations and moreover they are affected
by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be
treated with the common drugs, so that there have been long efforts to develop drugs to combat
that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in
cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective
efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those
inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4
we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a
MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition
of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active
compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant
anticancer drug as proof-of-principle to encourage for further preclinical studie