The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation

Igor Vivanco, Daniel Rohle, Matthias Versele, Akio Iwanami, Daisuke Kuga, Barbara Oldrini, Kazuhiro Tanaka, Julie Dang, Sara Kubek, Nicolaos Palaskas, Teli Hsueh, Michael Evans, David Mulholland, Daniel Wolle, Sigrid Rajasekaran, Ayyappan Rajasekaran, Linda M. Liau, Timothy F. Cloughesy, Ivan Dikic, Cameron BrennanHong Wu, Paul S. Mischel, Timothy Perera, Ingo K. Mellinghoff

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6459-6464
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number14
DOIs
Publication statusPublished - 2010 Apr 6

Keywords

  • Cbl
  • Drug resistance
  • Glioma
  • PTEN
  • Ubiquitylation

ASJC Scopus subject areas

  • General

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    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., ... Mellinghoff, I. K. (2010). The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation. Proceedings of the National Academy of Sciences of the United States of America, 107(14), 6459-6464. https://doi.org/10.1073/pnas.0911188107