Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib inEGFRWild-Type Non–Small Cell Lung Carcinoma Cell Lines

Angélique Augustin,David W Avila,Barbara Klughammer,Hanno Langen,Stefan Scheiblich,Manuel Tzouros,Hélène Meistermann,Sabrina Golling,Jens Lamerz,Laurent Essioux,Guillemette Duchateau-Nguyen,Johannes C Hermann

doi:10.1158/1535-7163.mct-12-0880

Angélique Augustin, David W Avila + Show 10 more

Open Access

https://doi.org/10.1158/1535-7163.mct-12-0880

Copy DOI

Abstract

Although both erlotinib and gefitinib target the EGF receptor (EGFR), erlotinib is effective in patients with EGFR wild-type or mutated tumors, whereas gefitinib is only beneficial for patients with activating mutations. To determine whether these differences in clinical outcomes can be attributed to their respective protein interaction profiles, a label-free, quantitative chemical proteomics study was conducted. Using this method, 24 proteins were highlighted in the binding profiles of erlotinib and gefitinib. Unlike gefinitib, erlotinib displaced the ternary complex formed by integrin-linked kinase (ILK), α-parvin, and PINCH (IPP). The docking of erlotinib in the three-dimensional structure of ILK showed that erlotinib has the ability to bind to the ATP-binding site, whereas gefitinib is unlikely to bind with high affinity. As the IPP complex has been shown to be involved in epithelial-to-mesenchymal transition (EMT) and erlotinib sensitivity has been correlated with EMT status, we used a cellular model of inducible transition and observed that erlotinib prevented EMT in a more efficient way than gefitinib by acting on E-cadherin expression as well as on IPP levels. A retrospective analysis of the MERIT trial indicated that, besides a high level of E-cadherin, a low level of ILK could be linked to clinical benefit with erlotinib. In conclusion, we propose that, in an EGFR wild-type context, erlotinib may have a complementary mode of action by inhibiting IPP complex activities, resulting in the slowing down of the metastatic process of epithelial tumors.

Highlights

Over the past few years, several drugs targeting protein kinases have shown clinical efficacy as cancer therapy [1]
A quantitative chemical proteomics method was applied to erlotinib and gefitinib (Fig. 1A) using the same wild-type EGF receptor (EGFR)-expressing non–small cell lung carcinoma (NSCLC) cell line H292 as biological target to identify the interaction profiles of the compounds
Nine proteins were found with an adjusted P value below 5% in the samples displaced with erlotinib (Fig. 1B, Regions A, B and x-axis; Supplementary Table S2), and 19 in those displaced with gefitinib (Fig. 1B; regions A, C, and y-axis; Supplementary Table S2), including EGFR, which was displaced by both compounds, confirming the validity of the approach

Summary

Introduction

Over the past few years, several drugs targeting protein kinases have shown clinical efficacy as cancer therapy [1]. Recent clinical data have shown that patients with non–small cell lung carcinoma (NSCLC) whose tumors harbor an activating EGFR mutation respond especially well to treatment with these TKIs [3, 4, 6]. Both TKIs target EGFR and are espe-. Authors' Affiliations: 1Protein and Metabolite Biomarkers, 2Bioinformatics and Exploratory Data Analysis, Translational Research Sciences, and 3Tarceva Clinical Biomarker Subteam, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland; 4Discovery Research Oncology, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Penzberg, Germany; and 5Discovery Chemistry, Pharmaceuticals Division, F.

Methods

Results

Conclusion