Lung cancer represents the largest cause of cancer-related mortality worldwide. Despite advancements in lung cancer treatment, relapse remains common and is partly mediated by a rare subpopulation of cells called drug-tolerant persisters (DTPs). DTPs survive by entering a stem cell-like state and later gain mutations via adaptive mutability to become genetically drug resistant. While long non-coding RNAs (lncRNAs) are known to contribute to drug resistance in lung cancers, the contribution of lncRNAs to drug tolerance has yet to be investigated.
We generated DTPs in EGFR-mutant PC-9 cells and KRASG12C-mutant H358 cells by treating with >IC90 osimertinib or sotorasib, respectively, for 3, 7 and 19 days. The DTPs from both cell lines expressed increased levels of stem cell factors (list) and previously described markers of minimal residual disease (list here). Error-prone polymerases were also increased in the DTPs from both cell lines. We next measured levels of MALAT1, NEAT1 and UFC1 as these lncRNAs are reported to be involved in stem cycle gene regulation as well as in the processes behind drug resistance. The expression of these lncRNAs was increased in DTPs after drug treatment for 3, 7 or 19 days: MALAT1 (1.7 to 3-fold in PC9 and 1.6-1.9-fold in H358), NEAT1 (1.8 to 2.7-fold in PC9 and 1.1 to 1.6-fold in H358), and UFC1 (1.8 to 2.7-fold in PC9 cells 1.8 to 4-fold in H358).
These results represent the first link between lncRNA expression and drug tolerance in lung cancer, with functional studies currently underway. A better understanding of the role of lncRNAs in drug tolerance has the potential to identify new approaches to prevent the emergence of drug resistance in lung cancer patients.