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

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.

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

“…Considering that a central feature of claudin-low TNBCs is the predominant expression of mesenchymal versus epithelial proteins, and given the known role of IL-8 in driving carcinoma mesenchymalization in several tumor types (22)(23)(24), the potential reversion of tumor phenotype upon neutralization of IL-8 with HuMax-IL8 was explored both in vitro and in vivo with the claudin-low cell lines MDA-MB-231 and MDA-MB-436. In vitro, a panel of epithelial-to-mesenchymal transition (EMT) markers was evaluated at the mRNA level in cells treated with HuMax-IL8 versus control IgG.…”

“…The widespread effects of IL-8 signaling at the tumor site via binding and signaling through the CXCR1 and CXCR2 receptors are twofold: (a) direct effects on tumor cell phenotype that lead to tumor mesenchymalization (13,14,24) and (b) chemotaxis of immune cells, resulting in the recruitment of suppressive MDSC populations (27). Both effects can contribute to therapeutic resistance and cancer progression.…”

Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer

“…Several reports have now demonstrated that these tumors frequently exhibit features of tumor initiating cells (also designated as cancer stem cells), upregulation of mesenchymal markers and downregulation of epithelial markers, thus suggesting a possible link between the phenomenon of epithelial-mesenchymal transition (EMT) and TNBC (Gupta and Massague 2006; Jeong, et al 2012; Sarrio, et al 2008). EMT has been associated with a more invasive or metastatic tumor behavior and with the acquisition of resistance to a variety of anti-cancer therapies, including chemotherapy, radiation, small molecule-targeted therapies and immunotherapy (Creighton, et al 2009; David, et al 2016; Fernando, et al 2016; Hamilton, et al 2014; Huang, et al 2013; Kalluri and Weinberg 2009; Larocca, et al 2013; Thiery and Sleeman 2006). …”

Epithelial-mesenchymal transition and inflammation at the site of the primary tumor

“…In particular, multiple reports have now demonstrated that acquisition of lung cancer resistance to EGFR inhibition is associated, in a subset of patients, with the occurrence of EMT [97–100]. Furthermore, several recent reports have implicated the IL-8/IL-8R axis in the resistance of lung cancer to the widely used EGFR tyrosine kinase inhibitors gefitinib [101] and erlotinib [102]. Observed among various preclinical model systems, lung cancer cells resistant to EGFR inhibition have been shown to transition into a mesenchymal-like phenotype while simultaneously upregulating the expression of both IL-6 and IL-8.…”

“…Observed among various preclinical model systems, lung cancer cells resistant to EGFR inhibition have been shown to transition into a mesenchymal-like phenotype while simultaneously upregulating the expression of both IL-6 and IL-8. Interestingly, blockade of IL-8 signaling was shown to effectively reduce the mesenchymal features of erlotinib-resistant cells, and more importantly, to markedly enhance their susceptibility to erlotinib or to chemotherapies [102]. Work from Liu and colleagues also revealed a central role for the chemokine IL-8 in tumor resistance to the EGFR inhibitor gefitinib [101].…”