Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors.
Open accessPublished version of a preprint
Abstract
Abstract The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP–ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non–small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Significance: Our study identifies activated ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. Cancer Discov; 2(10); 934–47. ©2012 AACR. Read the Commentary on this article by Blakely and Bivona, p. 872. This article is highlighted in the In This Issue feature, p. 857.
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In rats, gefitinib reached a maximum brain-to-blood ratio of only 0.2.
“This is in contrast to [14C]gefitinib which had a maximum brain-to-blood ratio of only 0.2 (60).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [60]
Prior chronic-exposure studies identified reactivation of MAPK and IGF1R signaling as mechanisms of acquired resistance to WZ4002.
“Prior studies, using chronic exposure models, have identified reactivation of mitogen activated protein kinase (MAPK) signaling and insulin like growth factor 1 (IGF1R) signaling as mechanisms of acquired resistance to WZ4002 (19, 20).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [19]
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- Authors
- Ercan, D., Xu, C., Yanagita, M., Monast, C. S., Pratilas, C. A., Montero, J., Butaney, M., Shimamura, T., Sholl, L., Ivanova, E. V., Tadi, M., Rogers, A., Repellin, C., Capelletti, M., Maertens, O., Goetz, E. M., Letai, A., Garraway, L. A., Lazzara, M. J., Rosen, N., Gray, N. S., Wong, K.-K., & Jänne, P. A.
- Affiliations
- Broad Institute (US)
- Authors' Affiliations: 1Lowe Center for Thoracic Oncology, 2Center for Cancer Genome Discovery, 3Department of Medical Oncology, 4Department of Cancer Biology, and 5Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute; 6Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Departments of 7Medicine, 8Pathology, and 9Genetics Division, Brigham and Women's Hospital, Boston; 10Broad Institute of Harvard and MIT, Cambridge, Massachusetts; 11Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania; Departments of 12Pediatrics, 13Medicine, and 14Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York; and 15Department of Molecular Pharmacology and Therapeutics, Oncology Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois
- ORCID
- Venue
- Cancer Discovery
- Published
- 2012-10-01
- Volume
- 2
- Issue
- 10
- Pages
- 934-947
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3477553
- OpenAlex
- W2169460814
- Cited by
- 294
- References
- 49
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 9 · 2023: 23 · 2022: 13 · 2021: 19 · 2020: 10 · 2019: 25 · 2018: 23 · 2017: 25 · 2016: 35 · 2015: 35 · 2014: 28 · 2013: 22 · 2012: 3
- FWCI
- 22.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (IRG-78-002-30, PO1 CA154303)
- Foundation Medicine
- National Cancer Institute (IRG-78-002-30, R01CA114465, P50CA090578, R01CA135257, P01CA154303, K08CA127350, PO1CA154303)
- 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 › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- EGFR kinase inhibitors, drug resistance, ERK signaling, MEK inhibition, WZ4002, erlotinib, T790M mutation, non-small cell lung cancer, EGFR internalization, combination therapy
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Acrylamides, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Pyrimidines, Quinazolines, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, Molecular Targeted Therapy, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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