title: Cancer cells harboring MET gene amplification activate alternative signaling pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors.
abstract: Hepatocyte growth factor/scatter factor (HGF/SF) receptor c-Met is implicated in growth, invasion and metastasis of many tumors. Tumor cells harboring MET gene amplification are initially sensitive to c-Met tyrosine kinase inhibitors (TKI), but escape from long-term treatment has not been investigated. C-Met is a client of heat shock protein 90 (Hsp90) and is destabilized by Hsp90 inhibitors, suggesting that these drugs may inhibit tumors driven by MET amplification, although tumor escape under these conditions also has not been explored. Here, we evaluated the initial inhibitory effects of, and the likelihood of escape from, the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) and the c-Met TKI SU11274, using two cell lines harboring MET gene amplification. 17-AAG inhibited cell growth in both cell lines and induced substantial apoptosis, whereas SU11274 was only growth inhibitory in one cell line. In both cell lines, c-Met-dependent Akt, Erk and/or STAT3 signaling, as well as activation of the EGFR family, resumed shortly after treatment with c-Met TKI despite sustained c-Met inhibition. PKC delta upregulation may participate in reactivation of c-Met downstream signaling in both cell lines. In contrast to c-Met TKI, 17-AAG destabilized c-Met protein and durably blocked reactivation of downstream signaling pathways and EGFR family members. Our data demonstrate that downstream signaling in tumor cells overexpressing c-Met is not stably suppressed by c-Met TKI, even though c-Met remains fully inhibited. In contrast, Hsp90 inhibitors provide long-lasting suppression of c-Met-dependent signaling, and these drugs should be further evaluated in tumors driven by MET gene amplification.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Suiquan
authors.initials: S
authors.lastname: Wang
authors.forename: Itai
authors.initials: I
authors.lastname: Pashtan
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Wanping
authors.initials: W
authors.lastname: Xu
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
mesh_terms: D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology*; D005784:Gene Amplification; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051745:Protein Kinase C-delta / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D047029:Lactams, Macrocyclic; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; C112765:tanespimycin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta