Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway.
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Abstract
The clinical efficacy of EGF receptor (EGFR) kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M-mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study, we develop drug-resistant versions of the EGFR-mutant PC9 cell line, which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804-resistant nor WZ4002-resistant clones of PC9 harbor EGFR T790M. Instead, they have shown activated insulin-like growth factor receptor (IGF1R) signaling as a result of loss of expression of IGFBP3 with the IGF1R inhibitor, BMS 536924, restoring EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug-resistant subclone that exhibits ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to the EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug-resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR-mutant non-small cell lung cancer. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways that become activated in resistant cancers, may be a more effective clinical strategy.
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Patients with EGFR-mutant tumors frequently progress on TKI therapy because secondary brain metastases grow.
“Patients harboring EGFRm+ tumors often progress during TKI treatment due to growth of secondary brain metastases (BM) (59).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [59]
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 [20]
In resistance mediated by IGF-IR and AXL, inhibition of the bypass RTK in combination with EGFR is needed to overcome resistance.
“In similar examples of resistance mediated by IGF-IR and AXL, inhibition of the bypass RTK in combination with the EGFR is needed to overcome resistance (Cortot et al., 2013; Guix et al., 2008; Zhang et al., 2012).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Cortot et al., 2013
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- Authors
- Cortot, A. B., Repellin, C. E., Shimamura, T., Capelletti, M., Zejnullahu, K., Ercan, D., Christensen, J. G., Wong, K.-K., Gray, N. S., & Jänne, P. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Authors' Affiliations: 1Lowe Center for Thoracic Oncology, 2Department of Medical Oncology, 3Belfer Institute for Applied Cancer Science; and 4Departments of Cancer Biology and 5Biological Chemistry and Molecular Pharmacology, Dana Farber Cancer Institute, 6Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and 7Department of Research Pharmacology, Pfizer Global Research and Development, La Jolla, California
- ORCID
- Venue
- Cancer Research
- Published
- 2013-01-15
- Volume
- 73
- Issue
- 2
- Pages
- 834-843
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3994895
- OpenAlex
- W2032397471
- Cited by
- 185
- References
- 36
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 12 · 2019: 9 · 2018: 15 · 2017: 23 · 2016: 18 · 2015: 30 · 2014: 22 · 2013: 20
- FWCI
- 18.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA114465, P50CA090578, R01CA135257)
- 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 tyrosine kinase inhibitors, drug resistance, T790M mutation, IGF1R signaling, WZ4002, BMS-536924, MEK inhibition, ERK activation, non-small cell lung cancer, gefitinib resistance, combination therapy, PC9 cell line
- MeSH terms
- Acrylamides, Humans, Lung Neoplasms, Pyrimidines, Receptor, IGF Type 1, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors, Quinazolinones
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