| Abstract: |
Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR- dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in 1 out of 24 primary EGER-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss. © 2009 American Association for Cancer Research. |
| Keywords: |
signal transduction; protein kinase b; controlled study; human cell; gene deletion; erlotinib; cluster analysis; gene expression; protein depletion; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; receptor, epidermal growth factor; enzyme activation; drug resistance, neoplasm; cell line, tumor; cancer resistance; protein kinase inhibitors; homozygosity; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; pten phosphohydrolase; gene loss; chromosome aberrations; quinazolines; mutant
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