title: HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells.
abstract: Tumor cells with genomic amplification of MET display constitutive activation of the MET tyrosine kinase, which renders them highly sensitive to MET inhibition. Several MET inhibitors have recently entered clinical trials; however, as with other molecularly targeted agents, resistance is likely to develop. Therefore, elucidating possible mechanisms of resistance is of clinical interest. We hypothesized that collateral growth factor receptor pathway activation can overcome the effects of MET inhibition in MET-amplified cancer cells by reactivating key survival pathways. Treatment of MET-amplified GTL-16 and MKN-45 gastric cancer cells with the highly selective MET inhibitor PHA-665752 abrogated MEK/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling, resulting in cyclin D1 loss and G(1) arrest. PHA-665752 also inhibited baseline phosphorylation of epidermal growth factor receptor (EGFR) and HER-3, which are transactivated via MET-driven receptor cross-talk in these cells. However, MET-independent HER kinase activation using EGF (which binds to and activates EGFR) or heregulin-beta1 (which binds to and activates HER-3) was able to overcome the growth-inhibitory effects of MET inhibition by restimulating MEK/MAPK and/or PI3K/AKT signaling, suggesting a possible escape mechanism. Importantly, dual inhibition of MET and HER kinase signaling using PHA-665752 in combination with the EGFR inhibitor gefitinib or in combination with inhibitors of MEK and AKT prevented the above rescue effects. Our results illustrate that highly targeted MET tyrosine kinase inhibition leaves MET oncogene-"addicted" cancer cells vulnerable to HER kinase-mediated reactivation of the MEK/MAPK and PI3K/AKT pathways, providing a rationale for combined inhibition of MET and HER kinase signaling in MET-amplified tumors that coexpress EGFR and/or HER-3.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachleitner-Hofmann
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Sun
authors.forename: Chin-Tung
authors.initials: CT
authors.lastname: Chen
authors.forename: Laura
authors.initials: L
authors.lastname: Tang
authors.forename: Lin
authors.initials: L
authors.lastname: Song
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.forename: Manish
authors.initials: M
authors.lastname: Shah
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D014162:Transfection
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; D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3; D020929:Mitogen-Activated Protein Kinase Kinases