Sensitization of EGFR Wild-Type Non-Small Cell Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitor Erlotinib

• Published in: Molecular cancer therapeutics Vol. 16; no. 8; pp. 1634 - 1644
• Main Authors: Raimbourg, Judith, Joalland, Marie-Pierre, Cabart, Mathilde, de Plater, Ludmilla, Bouquet, Fanny, Savina, Ariel, Decaudin, Didier, Bennouna, Jaafar, Vallette, François M, Lalier, Lisenn
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.08.2017
• Subjects: Activation; Animal models; Animals; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - metabolism; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Culture Media, Conditioned - pharmacology; Drug Resistance, Neoplasm - drug effects; Enzyme Activation - drug effects; Enzyme inhibitors; Epidermal growth factor receptors; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; In vivo methods and tests; Injections; Kinases; Ligands; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Markers; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Patients; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - drug effects; src-Family Kinases - metabolism; Therapy; Tumors; Tyrosine; Tyrosine kinase inhibitors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-17-0075

The benefit of EGFR-TKI in non-small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non-small cell lung cancer and the functional consequences and in animal models of patient-derived xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR-expressing cells to erlotinib, contrary to what happens in mutant EGFR cells and with a blocking EGFR antibody, both and The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers that enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, which should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy. .