ABSTRACT
Epidermal growth factor receptor (EGFR) exon 19 deletion is a major driver for the drug resistance of non-small cell lung cancer (NSCLC). Identification small inhibitor capable of selectively inhibiting EGFR-19del NSCLC is a desirable strategy to overcome drug resistance in NSCLC. This study aims to screen an inhibitor for EGFR exon 19 deletion cells and explore its underlying mechanism. High through-put screen was conducted to identify an inhibitor for EGFR-19del NSCLC cells. And tenovin-3 was identified as a selective inhibitor of PC9 cells, an EGFR-19del NSCLC cells. Tenovin-3 showed particular inhibition effect on PC9 cells proliferation through inducing apoptosis and ferroptosis. Mechanistically, tenovin-3 might induce the apoptosis and ferroptosis of PC9 cells through mitochondrial pathway, as indicated by the change of VDAC1 and cytochrome c (cyt c). And bioinformatics analyses showed that the expression levels of SLC7A11 and CPX4 were correlated with NSCLC patient's survival. Our findings provide evidences for tenovin-3 to be developed into a novel candidate agent for NSCLC with EGFR exon 19 deletion. Our study also suggests that inducing ferroptosis may be a therapeutic strategy for NSCLC with EGFR exon 19 deletion.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Ferroptosis , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , ErbB Receptors/metabolism , Apoptosis , Cell Line, Tumor , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/pharmacology , MutationABSTRACT
When can children speaking Japanese, English, or Chinese map and extend novel nouns and verbs? Across 6 studies, 3- and 5-year-old children in all 3 languages map and extend novel nouns more readily than novel verbs. This finding prevails even in languages like Chinese and Japanese that are assumed to be verb-friendly languages (e.g., T. Tardif, 1996). The results also suggest that the input language uniquely shapes verb learning such that English-speaking children require grammatical support to learn verbs, whereas Chinese children require pragmatic as well as grammatical support. This research bears on how universally shared cognitive factors and language-specific linguistic factors interact in lexical development.
