Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors

Aarif Ahsan, Susmita G. Ramanand, Christopher Whitehead, Susan M. Hiniker, Alnawaz Rehemtulla, William B. Pratt, Shruti Jolly, Christopher Gouveia, Kristy Truong, Carter Van Waes, Dipankar Ray, Theodore S. Lawrence, Mukesh K. Nyati

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)670-677
Number of pages8
JournalNeoplasia (United States)
Volume14
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

Fingerprint

Dive into the research topics of 'Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors'. Together they form a unique fingerprint.

Cite this