Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib in EGFR Wild-type Non-small Cell Lung Carcinoma Cell Lines
Menée sur des lignées cellulaires de cancer du poumon non à petites cellules sans mutations du gène EGFR, cette étude met en évidence un mécanisme permettant de rendre compte de l'efficacité clinique de l'erlotinib, par comparaison avec le gefinitib qui n'est efficace qu'en présence de mutations activatrices du récepteur EGFR
Although both erlotinib and gefitinib target the epidermal growth factor 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 performed. 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), -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.
http://mct.aacrjournals.org/content/early/2013/01/31/1535-7163.MCT-12-0880.abstract