IL-8 signaling is involved in resistance of lung carcinoma cells to erlotinib

Autor: Romaine I. Fernando, Claudia Palena, Duane H. Hamilton, Charli Dominguez, Justin M. David, Kristen K. McCampbell
Rok vydání: 2015
Předmět:
0301 basic medicine
erlotinib
Lung Neoplasms
Pharmacology
p38 Mitogen-Activated Protein Kinases
Mice
0302 clinical medicine
Carcinoma
Non-Small-Cell Lung
Epidermal growth factor receptor
Erlotinib Hydrochloride
biology
Gefitinib
Up-Regulation
ErbB Receptors
Phenotype
Oncology
030220 oncology & carcinogenesis
Female
Erlotinib
medicine.drug
Signal Transduction
Research Paper
Epithelial-Mesenchymal Transition
Mice
Nude
Antineoplastic Agents
03 medical and health sciences
Downregulation and upregulation
medicine
Animals
Humans
Epithelial–mesenchymal transition
Lung cancer
IL-8
business.industry
Interleukin-8
Cancer
medicine.disease
tumor resistance
respiratory tract diseases
030104 developmental biology
A549 Cells
Drug Resistance
Neoplasm
Mutation
Cancer research
biology.protein
Quinazolines
business
Neoplasm Transplantation
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: // Romaine I. Fernando 1 , Duane H. Hamilton 1 , Charli Dominguez 1 , Justin M. David 1 , Kristen K. McCampbell 1 , Claudia Palena 1 1 Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA Correspondence to: Claudia Palena, email: palenac@mail.nih.gov Keywords: erlotinib, tumor resistance, IL-8, epithelial-mesenchymal transition Received: October 02, 2015 Accepted: May 14, 2016 Published: May 27, 2016 ABSTRACT A signaling pathway that is frequently deregulated in human carcinomas and has been explored as a therapeutic target involves the activation of the epidermal growth factor receptor (EGFR). Inhibition of EGFR via the small molecule inhibitors erlotinib and gefitinib commonly results in tumor resistance, even in patients with EGFR-mutant tumors that initially show substantial clinical responses. This study was designed to broaden our understanding of the molecular mechanisms of acquired resistance to erlotinib in lung cancer cells bearing wild type or mutated EGFR. We report here that generation of erlotinib-resistant lung cancer cells in vitro resulted in a phenotypic alteration reminiscent of an epithelial-mesenchymal transition (EMT) concomitant with a robust upregulation of the IL-8/IL-8R axis. Our results also demonstrate that upregulation of p38 MAPK signaling is responsible for the enhanced IL-8 secretion in the erlotinib-resistant tumor cells. Blockade of IL-8 signaling effectively reduced mesenchymal features of the resistant cells and also markedly enhanced their susceptibility to erlotinib. These results provide a rationale for the development of new therapeutic approaches involving blockade of IL-8 signaling for the management of acquired resistance to EGFR inhibition in patients with lung cancer.
Databáze: OpenAIRE
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