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PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR
Open accessPublished version of a preprint
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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“Similarly, a report found that PTEN loss may be associated with resistance to EGFR inhibitors (Sos et al., 2009).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Sos et al., 2009
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Somatic mutations affect key pathways in lung adenocarcinoma
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Self-citationNegative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN
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Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer
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Self-citationMolecular determinants of the response of glioblastomas to EGFR kinase inhibitors
Mellinghoff, I. K., Wang, M. Y., Vivanco, I., Haas-Kogan, D. A., Zhu, S., Dia, E. Q., Lu, K. V., Yoshimoto, K., Huang, J. H. Y., Chute, D. J., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa051918 · Cited by 1,442
Characterizing the cancer genome in lung adenocarcinoma
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The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway
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Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., Orme, J. P., Finlay, M. R. V., Ward, R. A., Mellor, M. J., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0337 · Cited by 2,246
Self-citationBrastianos, P. K., Carter, S. L., Santagata, S., Cahill, D. P., Taylor-Weiner, A. N., Jones, R. T., Allen, E. M. V., Lawrence, M. S., Horowitz, P. M., Cibulskis, K., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0369 · Cited by 1,090
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083
“Similarly, loss of PTEN expression in EGFR -mutant cells correlates with decreased sensitivity to EGFR TKI”
BackgroundKinase drug discovery 20 years after imatinib: progress and future directions
Cohen, P., Cross, D. A. E., & Janne, P. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00195-4 · Cited by 1,092
The quest to overcome resistance to EGFR-targeted therapies in cancer
Chong, C. R., & Janne, P. A. (2013) · Nature Medicine · doi:10.1038/nm.3388 · Cited by 1,076
Metadata
- 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
- Venue
- Cancer Research
- Published
- 2009-04-15
- Volume
- 69
- Issue
- 8
- Pages
- 3256-3261
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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