Journal
PHARMACOLOGICAL RESEARCH
Volume 102, Issue -, Pages 132-137Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2015.09.022
Keywords
Non-small-cell lung cancer (NSCLC); Tyrosine kinase inhibitors (TKIs); Epidermal growth factor receptor (EGFR) inhibition; AKT protein kinase; Etc-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)
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Funding
- Joan and Irwin Jacobs Fund of the Jewish Community Foundation
- Daiichi-Sankyo
- American Head and Neck Society (Ballantyne Award)
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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. (C) 2015 Elsevier Ltd. All rights reserved.
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