The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation Journal Article
| Authors: | 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, L. M.; Cloughesy, T. F.; Dikic, I.; Brennan, C.; Wu, H.; Mischel, P. S.; Perera, T.; Mellinghoff, I. K. |
| Article Title: | The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation |
| 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 themolecular 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. |
| Keywords: | signal transduction; controlled study; human tissue; protein expression; human cell; glioma; phenotype; animals; mice; mice, knockout; imatinib; platelet derived growth factor alpha receptor; apoptosis; enzyme inhibition; protein degradation; protein targeting; epidermal growth factor receptor; cell line; protein binding; rna interference; receptor, epidermal growth factor; enzyme activation; drug resistance; phosphatidylinositol 3 kinase; protein kinase inhibitors; ubiquitination; enzyme inactivation; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; ligand; pten; cbl protein; proto-oncogene proteins c-cbl; concentration response; scatter factor receptor; cbl; ubiquitylation; n (3 chlorophenyl) 3 [3,5 dimethyl 4 (4 methyl 1 piperazinylcarbonyl) 1h pyrrol 2 ylmethylene] 2,3 dihydro n methyl 2 oxo 1h indole 5 sulfonamide; pelitinib |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 107 |
| Issue: | 14 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2010-04-06 |
| Start Page: | 6459 |
| End Page: | 6464 |
| Language: | English |
| DOI: | 10.1073/pnas.0911188107 |
| PUBMED: | 20308550 |
| PROVIDER: | scopus |
| PMCID: | PMC2851999 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus" |
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