Combination therapy with anti-ErbB3 monoclonal antibodies and EGFR TKIs potently inhibits Non-small Cell Lung Cancer

Alessia Noto,Pierpaolo Coluccia,Debora Malpicci,Gennaro Ciliberto,Emanuele Marra,Luigi Fattore,Antonio D’Andrilli,Luigi Aurisicchio,Laura Luberto,Maria Rosaria Giovagnoli,Claudia De Vitis,Nicola Normanno,Luigi Ruco,Giuseppe Roscilli,Rita Mancini

doi:10.18632/oncotarget.1141

Abstract

Personalized therapy of advanced non-small cell lung cancer (NSCLC) has been improved by the introduction of EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. EGFR TKIs induce dramatic objective responses and increase survival in patients bearing sensitizing mutations in the EGFR intracytoplasmic tyrosine kinase domain. However, virtually all patients develop resistance, and this is responsible for disease relapse. Hence several efforts are being undertaken to understand the mechanisms of resistance in order to develop combination treatments capable to sensitize resistant cells to EGFR TKIs. Recent studies have suggested that upregulation of another member of the EGFR receptor family, namely ErbB3 is involved in drug resistance, through increased phosphorylation of its intracytoplasmic domain and activation of PI3K/AKT signaling. In this paper we first show, by using a set of malignant pleural effusion derived cell cultures (MPEDCC) from patients with lung adenocarcinoma, that surface ErbB3 expression correlates with increased AKT phosphorylation. Antibodies against ErbB3, namely A3, which we previously demonstrated to induce receptor internalization and degradation, inhibit growth and induce apoptosis only in cells overexpressing surface ErbB3. Furthermore, combination of anti-ErbB3 antibodies with EGFR TKIs synergistically affect cell proliferation in vitro, cause cell cycle arrest, up-regulate p21 expression and inhibit tumor growth in mouse xenografts. Importantly, potentiation of gefitinib by anti-ErbB3 antibodies occurs both in de novo and in ab initio resistant cells. Anti-ErbB3 mAbs strongly synergize also with the dual EGFR and HER2 inhibitor lapatinib. Our results suggest that combination treatment with EGFR TKI and antibodies against ErbB3 should be a promising approach to pursue in the clinic.

Highlights

Lung cancer is the most commonly diagnosed type of cancer and the primary cause of cancer-related deaths worldwide [1,2]
epidermal growth factor receptor (EGFR) belongs to a family of four transmembrane receptors (ErbB2/HER2, ErbB3/HER3 and ErbB4), commonly called ErbBs which, upon ligand-driven homo or heterodimerization and subsequent activation of their receptor-associated tyrosine kinase domains, stimulate downstream signaling cascades leading to cell proliferation, motility and survival [7,8]
We first measured surface expression of ErbB3 by cytofluorimetry (Figure 1a, Table 1). To this purpose we utilized 7 malignant pleural effusion derived cell cultures (MPEDCC) and as control a stable lung Adeno Ca cell lines, PC9 which is highly sensitive to gefitinib (IC50 0,015 μM) for the presence of exon 19 deletion, and its gefitinib resistance subclone PC9ZD, which harbors the gatekeeper T790M (Table 1, Supplementary 1) [34,35]

Summary

Introduction

Lung cancer is the most commonly diagnosed type of cancer and the primary cause of cancer-related deaths worldwide [1,2]. Several Phase III clinical trials have shown statistically significant superiority to standard chemotherapy in terms of response rate, progressionfree survival and quality of life in patients with NSCLC across all therapy lines. In light of these studies TKIs like gefitinib can be considered as the standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations [5,14,15,16,17,18,19]

Methods

Results

Conclusion