ArticleOncoTargets and therapy2020
p70S6K Promotes Acquired Resistance of Erlotinib Through Induction of Epithelial-Mesenchymal Transition in Non-Small Cell Lung Carcinoma.
Article in OncoTargets and therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
2 citing papers in PubMed, 6 citations in OpenAlex.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLung cancer is the leading cause of cancer-related deaths. EGFR tyrosine kinase inhibitors, such as erlotinib, were approved for non-small cell lung carcinoma patients with EGFR mutations. However, the acquired resistance of these inhibitors has not been fully clarified. Therefore, clarifying the mechanism and developing new rationales to overcome the drug resistance are urgently needed.
methodsA pair of erlotinib sensitive and resistant cells was used to identify the key molecules in mediating erlotinib resistance. Loss- or gain-of-function study was used to confirm the effects of the key molecules. Xenograft mouse model and human cancer tissue sample studies were conducted for further corroboration.
resultsHCC827 cells with acquired resistance to erlotinib underwent epithelial-mesenchymal transition and exhibited enhanced p70S6K signaling compared to parental sensitive cells. Moreover, in erlotinib resistant cells, downregulation of p70S6K expression using either siRNA or shRNA reversed EMT and partially overcame erlotinib resistance. Meanwhile, in erlotinib sensitive cells, overexpression of p70S6K promoted EMT and induced erlotinib resistance. Upregulation of p70S6K signaling in erlotinib resistant cells was caused by reduced GSK3β-mediated protein degradation of mTOR and raptor. Additionally, p70S6K silencing suppressed the growth of erlotinib resistant cells in a xenograft mouse model. Finally, we found a correlation between p70S6K and E-cadherin expression in human non-small-cell lung cancer (NSCLC) tissue samples.
conclusionOur findings suggest that p70S6K-induced EMT plays an important role in the acquired resistance of erlotinib and provides a novel therapeutic rationale of targeting p70S6K in NSCLC therapy.
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