Resistance to Gefitinib in PTEN-Null HER-Overexpressing Tumor Cells Can Be Overcome through Restoration of PTEN Function or Pharmacologic Modulation of Constitutive Phosphatidylinositol 3′-Kinase/Akt Pathway Signaling

摘要: Purpose: Tyrosine kinase (TK) inhibitors are emerging as a promising new approach to the treatment of HER overexpressing tumors, however optimal use these agents awaits further definition downstream signaling pathways that mediate their effects. We reported previously both EGFR- and Her2-overexpressing tumors sensitive EGFR-selective TK inhibitor gefitinib (ZD1839, “Iressa”), sensitivity this agent correlated with its ability down-regulate Akt. However, EGFR-overexpressing MDA-468 cells, which lack PTEN function, resistant ZD1839, ZD1839 is unable Akt activity in cells. Experimental Design: To study role we generated MDA468 cells tet-inducible expression. Results: show here resistance attributable EGFR-independent constitutive activation caused by loss function Reconstitution through expression restores reestablishes EGFR-stimulated signaling. Although restoration difficult implement clinically, much effects overactive PI3K/Akt pathway signaling, overactivity can be modulated pharmacologic approaches. down-regulation using PI3K LY294002 similarly sensitizes ZD1839. Conclusions: Sensitivity requires intact growth factor receptor-stimulated activity. leads uncoupling results resistance, reversed reintroduction or These data have important predictive therapeutic clinical implications.