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.
Highlights
Acquisition of drug resistance is a common phenomenon observed during tumor progression
We have identified the activation of the IL-8/IL-8R axis in non-small cell lung carcinoma (NSCLC) cells as a novel mechanism involved in the acquisition of resistance to targeted inhibition of the epidermal growth factor receptor (EGFR) kinase
Blockade of the IL-8 signaling axis via the use of a neutralizing antibody directed against IL-8 resulted in the re-acquisition of epithelial features, sensitization to EGFR inhibition and re-establishment of cytotoxic responses to chemotherapy treatment, providing evidence for a potential approach to enhance clinical responses to EGFR TKIs in the clinic
Summary
Acquisition of drug resistance is a common phenomenon observed during tumor progression. In the case of non-small cell lung carcinoma (NSCLC), the presence of defined mutations in the EGFR kinase domain [3, 4], known as sensitizing mutations, substantially increases the response to treatment with the EGFR-specific small molecule inhibitors erlotinib and gefitinib [5,6,7]. Patients carrying these mutations respond favorably to EGFR inhibition, tumor relapse is common within one to two years of treatment due to acquired resistance to therapy [8]. Acquisition of resistance to EGFR inhibition would pose a significant challenge to treatment decisions
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