Fig. 1.

Lineage plasticity lead to TKI resistance in NSCLC. Upon targeted therapies, various molecular events can promote lineage plasticity, thereby driving intratumoural heterogeneity and drug resistance. RB1 and TP53 mutation or loss NSCLC cells are more likely to transdifferentiate into small cell tumors. Increased histone-modifying enzymes, such as enhancer of zeste homologue 2 (EZH2) and lineage-associated transcription factors, such as SOX family genes mediates the reprogramming of NSCLC into slow-cycling, drug-tolerant cell states. These slow-cycling, drug-tolerant cells generally present neuroendocrine differentiation and epithelial-to-mesenchymal transition (EMT). Alterations of key signaling pathways and crosstalk with the tumor microenvironment also control lineage plasticity. Collectively, the plasticity-permissive molecular environment under the pressure of targeted therapies trigger the intratumoural clones presenting an alternative histology to that initially diagnosed, which might become the predominant cell type and exhibit drug resistance. Blue font: lncRNA-mediated molecular events that promote lineage plasticity