title: Heat-shock protein 27 (HSP27, HSPB1) is up-regulated by MET kinase inhibitors and confers resistance to MET-targeted therapy.
abstract: The tyrosine kinase encoded by the MET oncogene is activated by gene mutation or amplification in tumors, which in most instances maintain addiction, i.e., dependency, to MET activation. This makes MET an attractive candidate for targeted therapies. Here we show that, in 3/3 MET-addicted human gastric cancer cell lines, MET kinase inhibition resulted in a 3- to 4-fold increased expression of the antiapoptotic small heat-shock protein of 27 kDa (HSP27, HSPB1). HSP27 increase depended on the inhibition of the MEK/ERK pathway and on heat-shock factor 1 (HSF1) and hypoxia-inducible factor-1α (HIF-1α) regulation. Importantly, HSP27-silenced MET-addicted cells underwent 2- and 3-fold more apoptosis following MET inhibition in vitro and in vivo, respectively. Likewise, in human cancer cells susceptible to epidermal growth factor receptor (EGFR) inhibition, EGFR inhibitors induced HSP27 expression and were strengthened by HSP27 suppression. In control cell lines that were not affected by drugs targeting MET or EGFR, these drugs did not induce HSP27 increase. Therefore, in cancer therapies targeting the MET pathway, the induction of HSP27 might limit the efficacy of anti-MET agents. As HSP27 increase also impairs the effectiveness of EGFR inhibitors and is known to protect cells from chemotherapeutics, the induction of HSP27 by targeted agents might strongly affect the success of combination treatments.
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy; Laboratory of Cancer Genetics.
authors.forename: Daniele
authors.initials: D
authors.lastname: Musiani
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy; Laboratory of Cancer Genetics.
authors.forename: John David
authors.initials: JD
authors.lastname: Konda
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy; Laboratory of Cancer Genetics.
authors.forename: Simona
authors.initials: S
authors.lastname: Pavan
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy; Laboratory of Cancer Genetics.
authors.forename: Erica
authors.initials: E
authors.lastname: Torchiaro
authors.affiliation: Laboratory of Molecular Pharmacology, and.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy; Laboratory of Vascular Oncology, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; and.
authors.forename: Alessio
authors.initials: A
authors.lastname: Noghero
authors.affiliation: Laboratory of Cancer Genetics.
authors.forename: Jessica
authors.initials: J
authors.lastname: Erriquez
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Timothy
authors.initials: T
authors.lastname: Perera
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy; Laboratory of Cancer Genetics.
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy; Laboratory of Cancer Genetics.
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: EGFR; hepatocyte growth factor receptor