Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6459-64. doi: 10.1073/pnas.0911188107. Epub 2010 Mar 22.
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.
磷酸酶和张力蛋白同源物（PTEN）是一种肿瘤抑制因子，在许多人类癌症中失活。PTEN 的缺失与表皮生长因子受体（EGFR）抑制剂的耐药性有关，但这种耐药性的分子基础尚不清楚。人们认为，通过多种受体酪氨酸激酶（RTKs）的未受抑制的磷脂酰肌醇-3-激酶（PI3K）激活可以使 PTEN 缺失的癌症摆脱对 EGFR 或任何其他单一 RTK 的“依赖性”以维持生存。在这里，我们报告了一种独特的耐药机制，即通过破坏新形成的泛素连接酶 Cbl 复合物的稳定性，PTEN 失活特异性地通过损害配体诱导的激活受体的泛素化和降解来提高 EGFR 活性。通过表达显性负性 Cbl，PTEN 相关的 EGFR 激酶抑制剂耐药性可被模拟，并且可通过更完全的 EGFR 激酶抑制来克服。PTEN 失活不会赋予对 MET 或 PDGFRA 激酶抑制剂的耐药性。我们的研究确定了 PTEN 在 EGFR 信号终止中的关键作用，并表明更有效的 EGFR 抑制应该可以克服由 PI3K 通路激活引起的耐药性。
