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 Journal Article
| Authors: | She, Q. B.; Solit, D.; Basso, A.; Moasser, M. M. |
| Article Title: | 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 |
| Abstract: | Purpose: Tyrosine kinase (TK) inhibitors are emerging as a promising new approach to the treatment of HER overexpressing tumors, however optimal use of these agents awaits further definition of the downstream signaling pathways that mediate their effects. We reported previously that both EGFR- and Her2-overexpressing tumors are sensitive to the new EGFR-selective TK inhibitor gefitinib (ZD1839, "Iressa"), and sensitivity to this agent correlated with its ability to down-regulate Akt. However, EGFR-overexpressing MDA-468 cells, which lack PTEN function, are resistant to ZD1839, and ZD1839 is unable to down-regulate Akt activity in these cells. Experimental Design: To study the role of PTEN function, we generated MDA468 cells with tet-inducible PTEN expression. Results: We show here that the resistance of MDA-468 cells to ZD1839 is attributable to EGFR-independent constitutive Akt activation caused by loss of PTEN function in these cells. Reconstitution of PTEN function through tet-inducible expression restores ZD1839 sensitivity to these cells and reestablishes EGFR-stimulated Akt signaling. Although restoration of PTEN function to tumors is difficult to implement clinically, much of the effects of PTEN loss are attributable to overactive PI3K/Akt pathway signaling, and this overactivity can be modulated by pharmacologic approaches. We show here that pharmacologic down-regulation of constitutive PI3K/Akt pathway signaling using the PI3K inhibitor LY294002 similarly restores EGFR-stimulated Akt signaling and sensitizes MDA-468 cells to ZD1839. Conclusions: Sensitivity to ZD1839 requires intact growth factor receptor-stimulated Akt signaling activity. PTEN loss leads to uncoupling of this signaling pathway and results in ZD1839 resistance, which can be reversed with reintroduction of PTEN or pharmacologic down-regulation of constitutive PI3K/Akt pathway activity. These data have important predictive and therapeutic clinical implications. |
| Keywords: | signal transduction; epidermal growth factor; protein kinase b; controlled study; human cell; proto-oncogene proteins; gene overexpression; epidermal growth factor receptor; down-regulation; drug effect; drug resistance, neoplasm; tumor cells, cultured; transfection; breast neoplasms; phosphatidylinositol 3 kinase; cancer resistance; protein tyrosine kinase inhibitor; gene expression regulation; gene activation; reverse transcriptase polymerase chain reaction; enzyme inhibitors; protein-serine-threonine kinases; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; chromones; morpholines; proto-oncogene proteins c-akt; gefitinib; gene loss; down regulation; receptor, erbb-2; quinazolines; drug sensitivity; phosphoric monoester hydrolases; genes, tumor suppressor; 2 morpholino 8 phenylchromone; phosphatidylinositol 3 kinase inhibitor; oncogene neu; repressor gene; growth factor receptor; humans; human; female; priority journal; article |
| Journal Title: | Clinical Cancer Research |
| Volume: | 9 |
| Issue: | 12 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2003-10-01 |
| Start Page: | 4340 |
| End Page: | 4346 |
| Language: | English |
| PUBMED: | 14555504 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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