Destabilization of the Epidermal Growth Factor Receptor (EGFR) by a Peptide That Inhibits EGFR Binding to Heat Shock Protein 90 and Receptor Dimerization

Abstract

Background: An eight-amino acid segment lying within the ␣C-␤4 loop region of many protein kinases determines sensitivity to Hsp90 inhibitors. Results: A peptide comprised of this segment of the EGFR inhibits both Hsp90 binding and EGF-dependent EGFR dimerization. Conclusion:The peptide selectively degrades EGFR versus other Hsp90 clients. Significance: This peptide represents a unique approach to the therapy of EGFR-driven tumors.

EGFR targeted therapies and radiation: Optimizing efficacy by appropriate drug scheduling and patient selection

“…In addition to forming a homodimer with itself, EGFR can dimerize with other receptor tyrosine kinases including Erb2, Erb3, and c-Met leading to downstream signal transduction (Mueller et al, 2010, Ahsan et al, 2014). Additionally, EGFR binds to the chaperone protein hsp90 promoting stability of the inactivated receptor (Ahsan et al, 2013). Recent studies suggest novel drugs that degrade EGFR are more effective than drugs that inhibit EGFR in preclinical models (Haglund et al, 2003, Zhuang et al, 2003, Feng et al, 2007, Kirisits et al, 2007, Ahsan et al, 2009, Ahsan et al, 2010).…”

“…The development of novel agents which target EGFR by different mechanisms such as receptor degradation and inhibition of dimerization may also be necessary to overcome resistance. Additionally, combinations of EGFR targeted therapies with other novel agents, such as drugs targeting hsp90, may improve the efficacy of these therapies (Ahsan et al 2013). …”

Localization of heat shock protein 110 in canine mammary gland tumors

“…Investigations of HSP90 are the most advanced, as this important chaperone molecule that regulates the folding and stability of a number of receptor tyrosine kinase proteins such as HER-2 or EGFR (Ahsan et al, 2013;Sidera et al, 2008). Since HER-2 plays an essential role in mammary tumorigenesis, HSP90 inhibitors that can induce HER-2 degradation and selectively eliminate cancer cells that express HER-2 on the cell surface membrane are greatly anticipated as novel mammary tumor therapies (Schulz et al, 2014).…”

Bacterial proteins and peptides in cancer therapy

“…Although few in number, there are indications that peptide therapy may have interesting potential in cancer therapy. For example, similar to small molecule inhibitors of tyrosine kinases targeting EGFR involved in proliferation and migration of cancer cells, a synthetic six amino acid peptide of the alphaC-beta4 loop region of EGFR has been shown to inhibit the dimerization and signaling activity of EGFR in the presence of its ligand 17 . This short peptide, targeting EGFR’s ATP-binding cleft and its dimerization face, additionally promotes EGFR interaction with the heat shock protein Hsp90, thereby catalyzing EGFR degradation as well 17 .…”

“…For example, similar to small molecule inhibitors of tyrosine kinases targeting EGFR involved in proliferation and migration of cancer cells, a synthetic six amino acid peptide of the alphaC-beta4 loop region of EGFR has been shown to inhibit the dimerization and signaling activity of EGFR in the presence of its ligand 17 . This short peptide, targeting EGFR’s ATP-binding cleft and its dimerization face, additionally promotes EGFR interaction with the heat shock protein Hsp90, thereby catalyzing EGFR degradation as well 17 . Indeed, several peptides such as Cilengitide, Trebananib, NGR-hTNF, Tyroserleutide, etc., are currently undergoing phase III clinical trials in patients with glioblastoma, ovarian, mesothelioma, or liver cancers 16 .…”