Abstract:
:The phosphatase and tensin homolog (PTEN) is a tumor suppressor that is inactivated in many human cancers. PTEN loss has been associated with resistance to inhibitors of the epidermal growth factor receptor (EGFR), but the molecular basis of this resistance is unclear. It is believed that unopposed phosphatidylinositol-3-kinase (PI3K) activation through multiple receptor tyrosine kinases (RTKs) can relieve PTEN-deficient cancers from their "dependence" on EGFR or any other single RTK for survival. Here we report a distinct resistance mechanism whereby PTEN inactivation specifically raises EGFR activity by impairing the ligand-induced ubiquitylation and degradation of the activated receptor through destabilization of newly formed ubiquitin ligase Cbl complexes. PTEN-associated resistance to EGFR kinase inhibitors is phenocopied by expression of dominant negative Cbl and can be overcome by more complete EGFR kinase inhibition. PTEN inactivation does not confer resistance to inhibitors of the MET or PDGFRA kinase. Our study identifies a critical role for PTEN in EGFR signal termination and suggests that more potent EGFR inhibition should overcome resistance caused by PI3K pathway activation.
journal_name
Proc Natl Acad Sci U S Aauthors
Vivanco I,Rohle D,Versele M,Iwanami A,Kuga D,Oldrini B,Tanaka K,Dang J,Kubek S,Palaskas N,Hsueh T,Evans M,Mulholland D,Wolle D,Rajasekaran S,Rajasekaran A,Liau LM,Cloughesy TF,Dikic I,Brennan C,Wu H,Mischel PS,doi
10.1073/pnas.0911188107subject
Has Abstractpub_date
2010-04-06 00:00:00pages
6459-64issue
14eissn
0027-8424issn
1091-6490pii
0911188107journal_volume
107pub_type
杂志文章abstract::The rate of reproduction of deep-sea bacteria from six different capture depths between 1957 and 10,476 meters was studied as a function of temperature and pressure. The results showed the following: the true deep-sea bacteria of different depths have several characteristics, presumably evolutionally derived, distingu...
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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