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

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