TY - JOUR
T1 - Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors
AU - Ahsan, Aarif
AU - Ramanand, Susmita G.
AU - Whitehead, Christopher
AU - Hiniker, Susan M.
AU - Rehemtulla, Alnawaz
AU - Pratt, William B.
AU - Jolly, Shruti
AU - Gouveia, Christopher
AU - Truong, Kristy
AU - Van Waes, Carter
AU - Ray, Dipankar
AU - Lawrence, Theodore S.
AU - Nyati, Mukesh K.
N1 - Funding Information:
Abbreviations: CHX, cycloheximide; GA, geldanamycin; EGFR, epidermal growth factor receptor; HSP90, heat shock protein 90; WT, wild-type Address all correspondence to: Mukesh K. Nyati, PhD, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109. E-mail: nyati@umich.edu 1This work was supported by R01CA131290, P50 CADE97248, Michigan Institute for Clinical and Health Research, University of Michigan Cancer Center support grant 5 P30 CA46592, and the James Stuart and Barbara Padnos Research Funds for Cancer Research (M.K. Nyati), NIDCD intramural program project ZIA-DC-000073 (C. Van Waes), and an Alfred Taubman Scholarship (T.S. Lawrence). 2This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.neoplasia.com. Received 20 June 2012; Revised 28 June 2012; Accepted 28 June 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.12986
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865263433&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865263433&partnerID=8YFLogxK
U2 - 10.1593/neo.12986
DO - 10.1593/neo.12986
M3 - Article
C2 - 22952420
AN - SCOPUS:84865263433
SN - 1522-8002
VL - 14
SP - 670
EP - 677
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 8
ER -