title: Elevated neutrophil gelatinase-associated lipocalin contributes to erlotinib resistance in non-small cell lung cancer.
abstract: OBJECTIVE
  The EGFR tyrosine kinase inhibitors (TKIs) demonstrate efficacy in NSCLC patients whose tumors harbor activating EGFR mutations. However, patients who initially respond to EGFR TKI treatment invariably develop resistance to the drugs. Known mechanisms account for approximately 70% of native and acquired EGFR TKI resistance. In the current study we investigated a novel mechanism of NSCLC resistance to erlotinib.
  
  
  METHODS
  The mechanisms of acquired erlotinib resistance were evaluated by microarray analysis in thirteen NSCLC cell lines and in vivo in mice. Correlations between plasma neutrophil gelatinase associated lipocalin (NGAL) levels, erlotinib response and the EGFR mutational status were assessed in advanced stage NSCLC patients treated with erlotinib.
  
  
  RESULTS
  In 5 of 13 NSCLC cell lines NGAL was significantly upregulated. NGAL knockdown in erlotinib-resistant cells increased erlotinib sensitivity in vitro and in vivo. NGAL overexpression in erlotinib-sensitive cells augmented apoptosis resistance. This was mediated by NGAL-dependent modulation of the pro-apoptotic protein Bim levels. Evaluation of the plasma NGAL levels in NSCLC patients that received erlotinib revealed that patients with lower baseline NGAL demonstrated a better erlotinib response. Compared to patients with wild type EGFR, patients with activating EGFR mutations had lower plasma NGAL at baseline and weeks 4 and 8.
  
  
  CONCLUSIONS
  Our studies uncover a novel mechanism of NGAL-mediated modulation of Bim levels in NSCLC that might contribute to TKI resistance in lung cancer patients. These findings provide the rationale for the further investigations of the utility of NGAL as a potential therapeutic target or diagnostic biomarker.
authors: Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA Los Angeles, CA.
authors: Kostyantyn
authors: K
authors: Krysan
authors: Xiaoyan
authors: X
authors: Cui
authors: Brian K
authors: BK
authors: Gardner
authors: Karen L
authors: KL
authors: Reckamp
authors: Xiaoyan
authors: X
authors: Wang
authors: Longsheng
authors: L
authors: Hong
authors: Tonya C
authors: TC
authors: Walser
authors: Nicole L
authors: NL
authors: Rodriguez
authors: Paul C
authors: PC
authors: Pagano
authors: Edward B
authors: EB
authors: Garon
authors: John F
authors: JF
authors: Brothers
authors: David
authors: D
authors: Elashoff
authors: Jay M
authors: JM
authors: Lee
authors: Avrum E
authors: AE
authors: Spira
authors: Sherven
authors: S
authors: Sharma
authors: Michael C
authors: MC
authors: Fishbein
authors: Steven M
authors: SM
authors: Dubinett
keywords: EGFR; Lung cancer; effectors of apoptosis; erlotinib resistance; survival factors
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