title: Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors.
abstract: The epidermal growth factor receptor (EGFR) has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key role in cell survival after chemotherapy and radiotherapy. Heat shock protein 90 (HSP90) is known to stabilize mutant EGFR and ErbB2, but its role in cancers with wild-type (WT) WT-EGFR is unclear. In this report, we demonstrate that fully mature, membrane-bound WT-EGFR interacts with HSP90 independent of ErbB2. Further, the HSP90 inhibitors geldanamycin (GA) and AT13387 cause a decrease in WT-EGFR in cultured head and neck cancer cells. This decrease results from a significantly reduced half-life of WT-EGFR. WT-EGFR was also lost in head and neck xenograft specimens after treatment with AT13387 under conditions that inhibited tumor growth and prolonged survival of the mice. Our findings demonstrate that WT-EGFR is a client protein of HSP90 and that their interaction is critical for maintaining both the stability of the receptor as well as the growth of EGFR-dependent cancers. Furthermore, these findings support the search for specific agents that disrupt HSP90's ability to act as an EGFR chaperone.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Aarif
authors.initials: A
authors.lastname: Ahsan
authors.forename: Susmita G
authors.initials: SG
authors.lastname: Ramanand
authors.forename: Christopher
authors.initials: C
authors.lastname: Whitehead
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hiniker
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: William B
authors.initials: WB
authors.lastname: Pratt
authors.forename: Shruti
authors.initials: S
authors.lastname: Jolly
authors.forename: Christopher
authors.initials: C
authors.lastname: Gouveia
authors.forename: Kristy
authors.initials: K
authors.lastname: Truong
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.forename: Dipankar
authors.initials: D
authors.lastname: Ray
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Nyati
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D006224:Cricetinae; D066246:ErbB Receptors / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D016227:Benzoquinones; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone; C001277:geldanamycin