Abstract
Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.
Highlights
Epidermal growth factor receptor (EGFR) is a molecular target of oncotherapy in certain kinds of cancer including non-small cell lung cancer (NSCLC) [1]
Our previous study showed that heregulin overexpression caused erlotinib resistance in EGFR mutant NSCLC cells [22]
We showed that in pre-clinical studies, afatinib can overcome the resistance to first generation EGFR-TKIs such as erlotinib in patients with heregulin-overexpressing NSCLCs
Summary
Epidermal growth factor receptor (EGFR) is a molecular target of oncotherapy in certain kinds of cancer including non-small cell lung cancer (NSCLC) [1]. EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib or erlotinib show drastic efficacy in patients with NSCLC harboring EGFR activating mutations [3, 4]. The constructive alteration of EGFR resulting from genomic mutation causes preferential ATP binding with its kinase domain and spontaneous EGFR activation. All patients become refractory to EGFR-TKI treatment after their initial response. Approximately 50% of patients with NSCLC harboring EGFR activating mutations were shown to have developed a T790M substitution EGFR secondary mutation upon their acquisition of resistance to EGFR-TKIs [6]. MET amplification, human EGFR 2 (HER2) amplification, or hepatocyte growth factor overexpression have been observed to cause EGFR-TKI resistance in NSCLC [7,8,9]. Current www.impactjournals.com/oncotarget clinical investigations seek to identify a novel treatment strategy for conquering EGFR-TKI resistance
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