Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy.

Abstract

Overexpression of ErbB-2/HER2 is associated with aggressive human malignancies, and therapeutic strategies targeting the oncoprotein are currently in different stages of clinical application. Tyrosine kinase inhibitors (TKIs) that block the nucleotide-binding site of the kinase are especially effective against tumors. Here we report an unexpected activity of TKIs: along with inhibition of tyrosine phosphorylation, they enhance ubiquitylation and accelerate endocytosis and subsequent intracellular destruction of ErbB-2 molecules. Especially potent is an irreversible TKI (CI-1033) that alkylates a cysteine specific to ErbB receptors. The degradative pathway stimulated by TKIs appears to be chaperone mediated, and is common to the heat shock protein 90 (Hsp90) antagonist geldanamycin and a stress-induced mechanism. In agreement with this conclusion, CI-1033 and geldanamycin additively inhibit tumor cell growth. Based upon a model for drug-induced degradation of ErbB-2, we propose a general strategy for selective destruction of oncoproteins by targeting their interaction with molecular chaperones.

• Authors: Ami Citri, Iris Alroy, Sara Lavi, Chanan Rubin, Wanping Xu, Nicolas Grammatikakis, Cam Patterson, Len Neckers, David W Fry, Yosef Yarden
• Journal: The EMBO journal (EMBO J) Vol. 21 Issue 10 Pg. 2407-17 (May 15 2002) ISSN: 0261-4189 [Print] England
• PMID: 12006493 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Benzoquinones
• Enzyme Inhibitors
• Lactams, Macrocyclic
• Morpholines
• Quinones
• Recombinant Proteins
• Ubiquitin
• Canertinib
• Protein-Tyrosine Kinases
• Receptor, ErbB-2
• geldanamycin

Topics

• Antineoplastic Agents (pharmacology)
• Benzoquinones
• Cell Division (drug effects)
• Cell Line
• Endocytosis
• Enzyme Inhibitors (pharmacology)
• Humans
• Lactams, Macrocyclic
• Morpholines (pharmacology)
• Neoplasms (drug therapy, pathology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinones (pharmacology)
• Receptor, ErbB-2 (drug effects, metabolism)
• Recombinant Proteins (metabolism)
• Transfection
• Ubiquitin (metabolism)