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

Martin L. Sos, Mirjam Koker, Barbara A. Weir, Stefanie Heynck, Rosalia Rabinovsky, Thomas Zander, Jens M. Seeger, Jonathan Weiss, Florian Fischer, Peter Frommolt, Kathrin Michel, Martin Peifer, Craig Mermel, Luc Girard, Michael Peyton, Adi F. Gazdar, John D. Minna, Levi A. Garraway, Hamid Kashkar, William PaoMatthew Meyerson, Roman K. Thomas

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372 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3256-3261
Number of pages6
JournalCancer research
Volume69
Issue number8
DOIs
StatePublished - Apr 15 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sos, M. L., Koker, M., Weir, B. A., Heynck, S., Rabinovsky, R., Zander, T., Seeger, J. M., Weiss, J., Fischer, F., Frommolt, P., Michel, K., Peifer, M., Mermel, C., Girard, L., Peyton, M., Gazdar, A. F., Minna, J. D., Garraway, L. A., Kashkar, H., ... Thomas, R. K. (2009). PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of akt and EGFR. Cancer research, 69(8), 3256-3261. https://doi.org/10.1158/0008-5472.CAN-08-4055