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.

journal_name

Neoplasia

authors

Ahsan A,Ramanand SG,Whitehead C,Hiniker SM,Rehemtulla A,Pratt WB,Jolly S,Gouveia C,Truong K,Van Waes C,Ray D,Lawrence TS,Nyati MK

doi

10.1593/neo.12986

subject

Has Abstract

pub_date

2012-08-01 00:00:00

pages

670-7

issue

8

eissn

1522-8002

issn

1476-5586

journal_volume

14

pub_type

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