Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib

Abstract

Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.

Drug Resistance to EGFR Inhibitors in Lung Cancer

“…Recently, a common mechanism of acquired resistance to EGFR TKIs has been reported as a result of an RTK switch, such as amplification of MET [50,51] or HER2 [52, 53] or activation of HER3 [75, 76], insulin-like growth factor 1 receptor (IGF-1R) [77, 78], or fibroblast growth factor receptor 1 (FGFR1) [79, 80]. …”

“…HER3 is activated independent of MET amplification in NSCLCs, and may contribute acquired drug resistance to EGFR TKI [75, 76]. HER3 lacks several catalytically important residues and is thought to be an inactive pseudokinase [82].…”

“…In NSCLC cells, HER3 couples with EGFR to activate the PI3K/AKT pathway in gefitinib-sensitive NSCLC cell lines, but not gefitinib-resistant lines, suggesting that NRG1-bound HER3 may predominantly dimerize with RTKs other than EGFR to promote acquired resistance to TKIs [76]. This mechanism may provide a rationale for the combined treatment of NSCLC patients with erlotinib and patritumab, an anti-HER3 monoclonal antibody [86].…”

From Proteomic Analysis to Potential Therapeutic Targets: Functional Profile of Two Lung Cancer Cell Lines, A549 and SW900, Widely Studied in Pre-Clinical Research

“…In spite of that, genes implicated in the emergence and progression of cancer have similar expression patterns in cancer cell lines and tumors, which validate the usefulness of the cell lines as an in vitro model of the tumors. The A549 adenocarcinoma and the SW900 squamous carcinoma cell lines are among the most commonly studied in lung cancer research and are widely used in terms of basic mechanisms of lung cancer and as pre-clinical in vitro models for drug sensitivity and effectiveness[91–94]. Past studies have focused in the comparative characterization between lung tumors and the corresponding derived cell lines in terms of morphology, genotyping, gene expression and protein abundance[95–97].…”

Liposomal curcumin and its application in cancer

“…Even so, 5-year survival rate is only 16%, though new drugs of anti-lung cancer such as angiogenesis-targeted drugs, epidermal growth factor receptor (EGFR)-targeted drugs, protein peptides of anti-lung cancer and lung cancer antibody drugs were developed. [97][98][99][100][101][102] Recently, a study reported that nanoliposomes using sodium hyaluronate and trimethyl CS form polymer-glycerosomes that can effectively deliver CUR to lung so as to improve the therapeutic index of CUR. 103 Recently, many studies reported that CUR liposomes have anticancer activity.…”