title: The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and -resistant MET-driven tumor models.
abstract: The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving MET-targeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers.
authors.affiliation: Authors' Affiliations: Urologic Oncology Branch and Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; Departments of Urology, Biochemistry, and Molecular Biology, Cancer Research Institute, SUNY Upstate Medical University, Syracuse, New York; and Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Miyajima
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Carole
authors.initials: C
authors.lastname: Sourbier
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
authors.forename: Candy
authors.initials: C
authors.lastname: Rivas
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yoshida
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Manabu
authors.initials: M
authors.lastname: Tatokoro
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shinohara
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nonomura
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018841:HSP90 Heat-Shock Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles; D011725:Pyridines; C533237:STA 9090; D014230:Triazoles; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met