title: EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function.
abstract: Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.
authors.affiliation: Head and Neck Cancer Research Laboratory, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco (UCSF), CA 94115; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA 94158.
authors.forename: Janyaporn
authors.initials: J
authors.lastname: Phuchareon
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA 94158 mccormic@cc.ucsf.edu osamu.tetsu@ucsf.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
authors.affiliation: Head and Neck Cancer Research Laboratory, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco (UCSF), CA 94115; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA 94158.
authors.forename: David W
authors.initials: DW
authors.lastname: Eisele
authors.affiliation: Head and Neck Cancer Research Laboratory, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco (UCSF), CA 94115; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA 94158 mccormic@cc.ucsf.edu osamu.tetsu@ucsf.edu.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tetsu
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D016213:Cyclins; C494041:ETS1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D012333:RNA, Messenger; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D000077156:Gefitinib
keywords: EGFR inhibition; ERK1/2 paradoxical activation; innate drug resistance; nonsmall cell lung cancer; tyrosine kinase inhibitors