Cited by 509Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

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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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Sos, Martin L., Koker, Mirjam, Weir, Barbara A., Heynck, Stefanie, Rabinovsky, Rosalia, Zander, Thomas, Seeger, Jens M., Weiss, Jonathan, Fischer, Florian, Frommolt, Peter, Michel, Kathrin, Peifer, Martin, Mermel, Craig, Girard, Luc, Peyton, Michael, Gazdar, Adi F., Minna, John D., Garraway, Levi A., Kashkar, Hamid, Pao, William, Meyerson, Matthew, Thomas, Roman K.·2009·Cancer Research

DOI 10.1158/0008-5472.can-08-4055PMC PMC2849653

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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.

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Authors: 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., Pao, W., Meyerson, M., & Thomas, R. K.
Affiliations: Max Planck Society (DE)
Broad Institute (US)
Harvard University (US)
University of Cologne (DE)
The University of Texas Southwestern Medical Center (US)
Memorial Sloan Kettering Cancer Center (US)
ORCID: Sos, Martin L.
Rabinovsky, Rosalia
Zander, Thomas
Weiss, Jonathan
Frommolt, Peter
Michel, Kathrin
Peifer, Martin
Mermel, Craig
Girard, Luc
Peyton, Michael
Gazdar, Adi F.
Minna, John D.
Garraway, Levi A.
Kashkar, Hamid
Pao, William
Meyerson, Matthew
Thomas, Roman K.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2009-04-15
Volume: 69
Issue: 8
Pages: 3256-3261
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-08-4055
PMC: PMC2849653
OpenAlex: W2133488997
Cited by: 504
References: 21
Citations by year: 2026: 8 · 2025: 15 · 2024: 15 · 2023: 20 · 2022: 17 · 2021: 25 · 2020: 30 · 2019: 31 · 2018: 39 · 2017: 33 · 2016: 34 · 2015: 45 · 2014: 35 · 2013: 48 · 2012: 31
FWCI: 30.59
Type: journal article
Language: en
Update notices: correction (2025-03-03)
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Funders: National Cancer Institute (R01CA116020, (P50-CA70907, P50CA070907)
National Institute of General Medical Sciences (T32GM007753)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: PTEN loss, erlotinib resistance, EGFR-mutant lung cancer, non-small cell lung cancer, Akt signaling, EGFR activation, EGFR inhibition, T790M mutation, MET amplification
MeSH terms: Erlotinib Hydrochloride, Carcinoma, Non-Small-Cell Lung, Chromosome Aberrations, Enzyme Activation, Humans, Lung Neoplasms, Quinazolines, Gene Expression, Cluster Analysis, Gene Deletion, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, ErbB Receptors

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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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