AKT inactivation causes persistent drug tolerance to EGFR inhibitors. (December 2015)

• Record Type: Journal Article
• Authors: Tetsu, Osamu; Phuchareon, Janyaporn; Eisele, David W.; Hangauer, Matthew J.; McCormick, Frank
• Is Part Of: Pharmacological research. Volume 102(2015:Dec.)
• Page Start: 132
• Page End: 137
• Publication Date: 2015-12
• Subjects: SCLC small cell lung cancer -- NSCLC non-small-cell lung cancer -- TKIs tyrosine kinase inhibitors -- RTK receptor tyrosine kinase -- EGFR epidermal growth factor receptor -- IGF-1R insulin-like growth factor 1 receptor -- FGFR1 fibroblast growth factor receptor 1 -- HGF hepatocyte growth factor -- FGF fibroblast growth factor -- NRG1 neuregulin 1 -- DUSP6 dual specificity phosphatase 6 -- PTEN phosphatase and tensin homolog -- EMT epithelial-mesenchymal transition; Non-small-cell lung cancer (NSCLC) -- Tyrosine kinase inhibitors (TKIs) -- Epidermal growth factor receptor (EGFR) inhibition -- AKT protein kinase -- Ets-1 transcription factor -- Dual specificity phosphatase 6 (DUSP6) -- ERK1/2 paradoxical activation -- Bcl-2 interacting protein Bim -- Drug resistance -- Drug tolerant persister cells -- Gefitinib (Iressa) -- Erlotinib (Tarceva) -- Lapatinib (Tykerb) -- PD325901 -- Saracatinib (AZD0530); Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2015.09.022
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Drug resistance is a major obstacle to the success of EGFR-targeted therapy. We recently studied the mechanism by which a small subset of EGFR mutant lung cancer cells remains viable after EGFR inhibition. We found that this drug-tolerant subpopulation develops because EGFR inhibition prevents AKT activity and thus inactivates Ets-1 function. In this article, we discuss how changes in intrinsic cell signaling after EGFR inhibition open a new avenue to drug resistance in NSCLCs, and comment on combined TKI and MEK inhibitor treatment to reduce the probability of emergent resistance to EGFR TKIs.