This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-4055v1 69/8/3256    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sos, M. L. Articles by Thomas, R. K. Search for Related Content PubMed PubMed Citation Articles by Sos, M. L. Articles by Thomas, R. K.

PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR

¹ Max-Planck-Institute for Neurological Research with Klaus-Joachim Zülch Laboratories of the Max-Planck-Society and the Medical Faculty of the University of Köln, ² Department I of Internal Medicine and Center of Integrated Oncology, University of Köln, ³ Institute for Medical Microbiology, Immunology and Hygiene, and ⁴ Institute for Medical Statistics, Informatics and Epidemiolgy, Köln, Germany; ⁵ The Broad Institute of Harvard and MIT, Cambridge, Massachusetts; ⁶ Department of Medical Oncology and ⁷ Center for Cancer Genome Discovery, Dana-Farber Cancer-Institute, and ⁸ Department of Pathology, Harvard Medical School, Boston, Massachusetts; ⁹ Hamon Center for Therapeutic Oncology Research, and Departments of ¹⁰ Pathology and ¹¹ Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas; ¹² Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York; and ¹³ Chemical Genomics Center of the Max-Planck-Society, Dortmund, Germany

Requests for reprints: Roman K. Thomas, Max-Planck-Institute for Neurological Research, Gleueler Street 50, Cologne 50931, Germany. Phone: 49-221-472-6259; Fax: 49-221-472-6298; E-mail: nini{at}nf.mpg.de.

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. [Cancer Res 2009;69(8):3256–61]

This article has been cited by other articles:

				M. L. Sos, S. Fischer, R. Ullrich, M. Peifer, J. M. Heuckmann, M. Koker, S. Heynck, I. Stuckrath, J. Weiss, F. Fischer, et al. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer PNAS, October 27, 2009; 106(43): 18351 - 18356. [Abstract] [Full Text] [PDF]