title: MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors.
abstract: The establishment of the role of MET in human cancer has led to the development of small-molecule inhibitors, many of which are currently in clinical trials. Thus far, nothing is known about their therapeutic efficacy and the possible emergence of resistance to treatment, a problem that has been often observed with other receptor tyrosine kinase (RTK) inhibitors. To predict mechanisms of acquired resistance, we generated resistant cells by treating MET-addicted cells with increasing concentrations of the MET small-molecule inhibitors PHA-665752 or JNJ38877605. Resistant cells displayed MET gene amplification, leading to increased expression and constitutive phosphorylation of MET, followed by subsequent amplification and overexpression of wild-type (wt) KRAS. Cells harboring KRAS amplification progressively lost their MET dependence and acquired KRAS dependence. Our results suggest that MET and KRAS amplification is a general mechanism of resistance to specific MET inhibitors given that similar results were observed with two small inhibitors and in different cell lines of different histotypes. To our knowledge, this is the first report showing that overexpression of wt KRAS can overcome the inhibitory effect of a RTK inhibitor. In view of the fact that cellular models of resistance to inhibitors targeting other tyrosine kinases have predicted and corroborated clinical findings, our results provide insights into strategies for preventing and/or overcoming drug resistance.
authors.affiliation: Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Turin, Italy. silvia.giordano@unito.it
authors.forename: Virna
authors.initials: V
authors.lastname: Cepero
authors.forename: J Rafael
authors.initials: JR
authors.lastname: Sierra
authors.forename: Simona
authors.initials: S
authors.lastname: Corso
authors.forename: Elena
authors.initials: E
authors.lastname: Ghiso
authors.forename: Laura
authors.initials: L
authors.lastname: Casorzo
authors.forename: Tim
authors.initials: T
authors.lastname: Perera
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D007211:Indoles; C000599304:JNJ38877605; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011724:Pyridazines; D017978:Receptors, Growth Factor; D013450:Sulfones; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins