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 Pao; Matthew Meyerson; Roman K. Thomas

doi:10.1158/0008-5472.CAN-08-4055

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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454 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 language	English (US)
Pages (from-to)	3256-3261
Number of pages	6
Journal	Cancer research
Volume	69
Issue number	8
DOIs	https://doi.org/10.1158/0008-5472.CAN-08-4055
State	Published - Apr 15 2009

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/0008-5472.CAN-08-4055

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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

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 2009, 'PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of akt and EGFR', Cancer research, vol. 69, no. 8, pp. 3256-3261. https://doi.org/10.1158/0008-5472.CAN-08-4055

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

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.",

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

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AU - Sos, Martin L.

AU - Koker, Mirjam

AU - Weir, Barbara A.

AU - Heynck, Stefanie

AU - Rabinovsky, Rosalia

AU - Zander, Thomas

AU - Seeger, Jens M.

AU - Weiss, Jonathan

AU - Fischer, Florian

AU - Frommolt, Peter

AU - Michel, Kathrin

AU - Peifer, Martin

AU - Mermel, Craig

AU - Girard, Luc

AU - Peyton, Michael

AU - Gazdar, Adi F.

AU - Minna, John D.

AU - Garraway, Levi A.

AU - Kashkar, Hamid

AU - Pao, William

AU - Meyerson, Matthew

AU - Thomas, Roman K.

PY - 2009/4/15

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AB - 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.

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

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