Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy.
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.
Citri
Ami
A
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Alroy
Iris
I
Lavi
Sara
S
Rubin
Chanan
C
Xu
Wanping
W
Grammatikakis
Nicolas
N
Patterson
Cam
C
Neckers
Len
L
Fry
David W
DW
Yarden
Yosef
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic; D009025:Morpholines / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D009025:Morpholines; D011505:Protein-Tyrosine Kinases; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D025801:Ubiquitin; C420268:Canertinib; C001277:geldanamycin