title: AKT inactivation causes persistent drug tolerance to EGFR inhibitors.
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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA, USA. Electronic address: Osamu.Tetsu@ucsf.edu.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tetsu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Janyaporn
authors.initials: J
authors.lastname: Phuchareon
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Eisele
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hangauer
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004361:Drug Tolerance / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT protein kinase; Bcl-2 interacting protein Bim; Drug resistance; Drug tolerant persister cells; Dual specificity phosphatase 6 (DUSP6); ERK1/2 paradoxical activation; Epidermal growth factor receptor (EGFR) inhibition; Erlotinib (Tarceva); Ets-1 transcription factor; Gefitinib (Iressa); Lapatinib (Tykerb); Non-small-cell lung cancer (NSCLC); PD325901; Saracatinib (AZD0530); Tyrosine kinase inhibitors (TKIs)