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

Igor Vivanco(Memorial Sloan Kettering Cancer Center), Daniel Rohle(Memorial Sloan Kettering Cancer Center), Matthias Versele, Akio Iwanami(University of California, Los Angeles), Daisuke Kuga(University of California, Los Angeles), Barbara Oldrini(Memorial Sloan Kettering Cancer Center), Kazuhiro Tanaka(University of California, Los Angeles), Julie Dang(University of California, Los Angeles), Sara Kubek(Memorial Sloan Kettering Cancer Center), Nicolaos Palaskas(University of California, Los Angeles), Teli Hsueh(University of California, Los Angeles), Michael J. Evans(Memorial Sloan Kettering Cancer Center), David J. Mulholland(University of California, Los Angeles), Daniel Wolle(Alfred I. duPont Hospital for Children), Sigrid A. Rajasekaran(Alfred I. duPont Hospital for Children), Ayyappan K. Rajasekaran(Alfred I. duPont Hospital for Children), Linda M. Liau(University of California, Los Angeles), Timothy F. Cloughesy(University of California, Los Angeles), Ivan Đikić(Goethe University Frankfurt), Cameron Brennan(Memorial Sloan Kettering Cancer Center), Hong Wu(University of California, Los Angeles), Paul S. Mischel(University of California, Los Angeles), Timothy Perera, Ingo K. Mellinghoff(Memorial Sloan Kettering Cancer Center)
Proceedings of the National Academy of Sciences
March 22, 2010
10.1073/pnas.0911188107
Cited by 105Open Access
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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.

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