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Am J Transl Res 2013;5(5):481-496
Original Article
Elevated neutrophil gelatinase-associated lipocalin contributes to
erlotinib resistance in non-small cell lung cancer
Kostyantyn Krysan, Xiaoyan Cui, Brian K Gardner, Karen L Reckamp, Xiaoyan Wang, Longsheng Hong, Tonya C
Walser, Nicole L Rodriguez, Paul C Pagano, Edward B Garon, John F II Brothers, David Elashoff, Jay M Lee,
Avrum E Spira, Sherven Sharma, Michael C Fishbein, Steven M Dubinett
Jonsson Comprehensive Cancer Center; Departments of Biostatistics, Pathology and Laboratory Medicine,
Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA; West Los
Angeles VA Healthcare System, Los Angeles, CA; City of Hope Comprehensive Cancer Center, Duarte, CA;
Boston University, Boston, MA. These authors contributed equally to this work.
Received May 31, 2013; Accepted June 10, 2013; Epub August 15, 2013; Published August 30, 2013
Abstract: Purpose: 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. Experimental Design: 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. (AJTR1305012).
Keywords: Lung cancer, effectors of apoptosis, survival factors, EGFR, erlotinib resistance
Address correspondence to: Dr. Steven M Dubinett, Division of Pulmonary and Critical Care Medicine, Clinical
Immunology & Allergy, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Room 37-131 CHS,
Box 951690, Los Angeles, CA 90095, USA. Tel: 310-825-5316; Fax: 310-206-8622; E-mail:
SDubinett@mednet.ucla.edu
Original Article
Elevated neutrophil gelatinase-associated lipocalin contributes to
erlotinib resistance in non-small cell lung cancer
Kostyantyn Krysan, Xiaoyan Cui, Brian K Gardner, Karen L Reckamp, Xiaoyan Wang, Longsheng Hong, Tonya C
Walser, Nicole L Rodriguez, Paul C Pagano, Edward B Garon, John F II Brothers, David Elashoff, Jay M Lee,
Avrum E Spira, Sherven Sharma, Michael C Fishbein, Steven M Dubinett
Jonsson Comprehensive Cancer Center; Departments of Biostatistics, Pathology and Laboratory Medicine,
Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA; West Los
Angeles VA Healthcare System, Los Angeles, CA; City of Hope Comprehensive Cancer Center, Duarte, CA;
Boston University, Boston, MA. These authors contributed equally to this work.
Received May 31, 2013; Accepted June 10, 2013; Epub August 15, 2013; Published August 30, 2013
Abstract: Purpose: 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. Experimental Design: 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. (AJTR1305012).
Keywords: Lung cancer, effectors of apoptosis, survival factors, EGFR, erlotinib resistance
Address correspondence to: Dr. Steven M Dubinett, Division of Pulmonary and Critical Care Medicine, Clinical
Immunology & Allergy, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Room 37-131 CHS,
Box 951690, Los Angeles, CA 90095, USA. Tel: 310-825-5316; Fax: 310-206-8622; E-mail:
SDubinett@mednet.ucla.edu
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