Elsevier

Neoplasia

Volume 14, Issue 8, August 2012, Pages 670-677, IN1
Neoplasia

Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors1,2

https://doi.org/10.1593/neo.12986Get rights and content
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open access

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.

Abbreviations

CHX
cycloheximide
GA
geldanamycin
EGFR
epidermal growth factor receptor
HSP90
heat shock protein 90
WT
wild-type

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1

This 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).

2

This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.neoplasia.com.