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

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

^* To whom correspondence should be addressed. E-mail: nini{at}nf.mpg.de.

	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 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]