期刊
CANCER RESEARCH
卷 69, 期 8, 页码 3256-3261出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-4055
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资金
- International Association for the Study of Lung Cancer
- Deutsche Krebshilfe [107954]
- Fritz-Thyssen-Stiftung [10.08.2.175]
- NGFN-Plus Program of the German Ministry of Science and Education [01GS08100]
- Specialized Programs of Research Excellence [P50CA70907]
- DOD PROSPECT
- Longenbaugh Foundation
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 I out of 24 primary EGFR-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss. [Cancer Res 2009;69(8):3256-61]
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