Oncotarget

Research Papers:

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

Romaine I. Fernando _, Duane H. Hamilton, Charli Dominguez, Justin M. David, Kristen K. McCampbell and Claudia Palena

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Oncotarget. 2016; 7:42031-42044. https://doi.org/10.18632/oncotarget.9662

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Abstract

Romaine I. Fernando1, Duane H. Hamilton1, Charli Dominguez1, Justin M. David1, Kristen K. McCampbell1, Claudia Palena1

1Laboratory 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.


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