PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.

Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, Michel K, Peifer M, Mermel C, Girard L, Peyton M, Gazdar AF, Minna JD, Garraway LA, Kashkar H, Pao W, Meyerson M, Thomas RK
Cancer Res. 2009 69 (8): 3256-61

PMID: 19351834 · PMCID: PMC2849653 · DOI:10.1158/0008-5472.CAN-08-4055

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 EGFR-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss.

MeSH Terms (16)

Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Chromosome Aberrations Cluster Analysis Drug Resistance, Neoplasm Enzyme Activation ErbB Receptors Erlotinib Hydrochloride Gene Deletion Gene Expression Humans Lung Neoplasms Protein Kinase Inhibitors Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Quinazolines

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