Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
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Abstract
Approximately half of EGFR-mutant non–small cell lung cancer (NSCLC) patients treated with small-molecule EGFR kinase inhibitors develop drug resistance associated with the EGF receptor (EGFR) T790M “gatekeeper” substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in preclinical models. However, these inhibitors have yet to prove clinically efficacious, and their toxicity in skin, reflecting activity against wild-type EGFR, may limit dosing required to effectively suppress EGFR T790M in vivo. While profiling sensitivity to various kinase inhibitors across a large cancer cell line panel, we identified indolocarbazole compounds, including a clinically well-tolerated FLT3 inhibitor, as potent and reversible inhibitors of EGFR T790M that spare wild-type EGFR. These findings show the use of broad cancer cell profiling of kinase inhibitor efficacy to identify unanticipated novel applications, and they identify indolocarbazole compounds as potentially effective EGFR inhibitors in the context of T790M-mediated drug resistance in NSCLC. Significance: EGFR-mutant lung cancer patients who respond to currently used EGFR kinase inhibitors invariably develop drug resistance, which is associated with the EGFR T790M resistance mutation in about half these cases. We unexpectedly identified a class of reversible potent inhibitors of EGFR T790M that do not inhibit wild-type EGFR, revealing a promising therapeutic strategy to overcome T790M-associated drug-resistant lung cancers. Cancer Discov; 3(2); 168–81. ©2012 AACR. See related commentary by Brewer and Pao, p. 138 This article is highlighted in the In This Issue feature, p. 125
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The T790M structural alteration enabled discovery of inhibitors that selectively inhibit T790M-bearing mutants, when in association with L858R or exon 19 deletions, relative to WT EGFR.
“Thus, the T790M structural alteration in essence “enabled” discovery of inhibitors that selectively inhibit T790M–bearing mutants, when in association with L858R or exon 19 deletions, relative to WT EGFR 58,59.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [59]
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- Authors
- Lee, H.-J., Schaefer, G., Heffron, T. P., Shao, L., Ye, X., Sideris, S., Malek, S., Chan, E., Merchant, M., La, H., Ubhayakar, S., Yauch, R. L., Pirazzoli, V., Politi, K., & Settleman, J.
- Affiliations
- Genentech (US)
- Corresponding author
- Settleman, Jeff
- ORCID
- Venue
- Cancer Discovery
- Published
- 2013-02-01
- Volume
- 3
- Issue
- 2
- Pages
- 168-181
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3576842
- OpenAlex
- W2085137844
- Cited by
- 90
- References
- 40
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 7 · 2019: 3 · 2018: 11 · 2017: 6 · 2016: 7 · 2015: 14 · 2014: 15 · 2013: 14
- FWCI
- 11.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Uniting Against Lung Cancer
- Yale University
- National Institutes of Health
- Genentech
- National Cancer Institute (R01CA120247, R00CA131488)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- T790M mutation, EGFR-mutant non-small cell lung cancer, EGFR kinase inhibitors, drug resistance, indolocarbazole, FLT3 inhibitors, covalent inhibitors, kinase inhibitor sensitivity
- MeSH terms
- Erlotinib Hydrochloride, Acrylamides, Animals, Base Sequence, Carbazoles, Humans, Lung, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Mice, Transgenic, Mutation, Pyrimidines, Quinazolines, Immunoblotting, Drug Resistance, Neoplasm, Staurosporine, Area Under Curve, Amino Acid Substitution, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, ErbB Receptors
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