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.
PURPOSE: The EGFR tyrosine kinase inhibitors (TKIs) demonstrate efficacy in NSCLCpatients 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 NSCLCpatients 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 NSCLCpatients 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 cancerpatients. These findings provide the rationale for the further investigations of the utility of NGAL as a potential therapeutic target or diagnostic biomarker.
Authors: King Pan Ng; Axel M Hillmer; Charles T H Chuah; Wen Chun Juan; Tun Kiat Ko; Audrey S M Teo; Pramila N Ariyaratne; Naoto Takahashi; Kenichi Sawada; Yao Fei; Sheila Soh; Wah Heng Lee; John W J Huang; John C Allen; Xing Yi Woo; Niranjan Nagarajan; Vikrant Kumar; Anbupalam Thalamuthu; Wan Ting Poh; Ai Leen Ang; Hae Tha Mya; Gee Fung How; Li Yi Yang; Liang Piu Koh; Balram Chowbay; Chia-Tien Chang; Veera S Nadarajan; Wee Joo Chng; Hein Than; Lay Cheng Lim; Yeow Tee Goh; Shenli Zhang; Dianne Poh; Patrick Tan; Ju-Ee Seet; Mei-Kim Ang; Noan-Minh Chau; Quan-Sing Ng; Daniel S W Tan; Manabu Soda; Kazutoshi Isobe; Markus M Nöthen; Tien Y Wong; Atif Shahab; Xiaoan Ruan; Valère Cacheux-Rataboul; Wing-Kin Sung; Eng Huat Tan; Yasushi Yatabe; Hiroyuki Mano; Ross A Soo; Tan Min Chin; Wan-Teck Lim; Yijun Ruan; S Tiong Ong Journal: Nat Med Date: 2012-03-18 Impact factor: 53.440
Authors: Karen L Reckamp; Marianna Koczywas; Mihaela C Cristea; Jonathan E Dowell; He-Jing Wang; Brian K Gardner; Ginger L Milne; Robert A Figlin; Michael C Fishbein; Robert M Elashoff; Steven M Dubinett Journal: Cancer Date: 2015-05-29 Impact factor: 6.860
Authors: E Massarelli; H Lin; L E Ginsberg; H T Tran; J J Lee; J R Canales; M D Williams; G R Blumenschein; C Lu; J V Heymach; M S Kies; V Papadimitrakopoulou Journal: Ann Oncol Date: 2015-05-29 Impact factor: 32.976
Authors: José Manuel Ruiz-Morales; Rita Dorantes-Heredia; Oscar Arrieta; Norberto C Chávez-Tapia; Daniel Motola-Kuba Journal: Tumour Biol Date: 2014-12-27