title: MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells.
abstract: Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30-40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Presutti
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Santini
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Cardinali
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Papoff
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lalli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Samperna
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fustaino
authors.affiliation: Department of Experimental Medicine, University La Sapienza, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy.
authors.forename: Giovina
authors.initials: G
authors.lastname: Ruberti
mesh_terms: D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C117307:KRAS protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human