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Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC
Open accessPublished version of a preprint
Abstract
Patients with non–small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFRT790M mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial–mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC. Significance: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the first drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR. Cancer Discov; 3(12); 1404–15. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 1317
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In the citing paper
“Rociletinib (XegafriTM, CO-1686) (65), developed by Clovis Oncology, is a specific mutant agent for the treatment of NSCLC, belonging to the third-generation EGFR TKIs.190,191”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [190]
In the citing paper
“Additionally, covalent inhibitors can exhibit high selectivity for proteins with non-conserved residues between variant forms or protein family members [41].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [41]
In the citing paper
“AZD9291 has a distinct chemical structure from the other third-generation TKIs, WZ4002 (34) and CO-1686 (35).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [35]
In the citing paper
“Indeed, pre-clinical reports have suggested that “third generation” agents can induce switching to multiple signaling mechanisms that bypass EGFR dependency such as ERK and AKT pathways (35, 61, 62).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [35]
In the citing paper
“Preclinical studies have confirmed that rociletinib has minimal activity against wild-type EGFR.7”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [7]
In the citing paper
“Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [7]
In the citing paper
“In xenograft models with EGFR-activating mutations alone or combined with T790M resistance mutations, rociletinib resulted in durable tumor shrinkage, 7 which was most marked when plasma concentrations were maintained at more than 200 ng per milliliter across the dosing interval.”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [7]
In the citing paper
“Rociletinib (CO-1686; Clovis Oncology) is a small-molecule, orally available, mutant-selective covalent inhibitor of commonly mutated forms of EGFR, including exon 19 deletions, L858R, and T790M, but not exon 20 insertions.”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [7]
In the citing paper
“Indeed, it seems that EGFR monoclonal antibodies 60 and EGFR WT kinase sparing covalent T790M selective TKIs 61 are ineffective in typical EGFR exon 20 insertion mutants.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [61]
In the citing paper
“Cysteine 797 is the site of covalent binding for all three of these agents (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [15]
In the citing paper
“They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [15]
In the citing paper
“These include the development of mutant selective EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, which to date have demonstrated encouraging efficacy in both preclinical models and in EGFR mutant NSCLC patients with EGFR T790M mediated drug resistance (14–18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [15]
In the citing paper
“CO-1686 is structurally more closely related to WZ4002 than to AZD9291 and in all of the models tested CO-1686 is very similar in vitro to WZ4002 (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [15]
In the citing paper
“Additional pre-clinical studies have also identified activation of MAPK signaling and IGF1R signaling as well as epithelial to mesenchymal (EMT) transition as potential resistance mechanisms to WZ4002 and CO-1686 (15, 19, 20).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [15]
In the citing paper
“In vitro and in vivo studies demonstrated that Rociletinib irreversibly and selectively inhibits mutant EGFR, including T790M mutation, with minimal activity against wild type EGFR, suggesting that drug tolerability to this agent may be superior to first and second generation EGFR inhibitors”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [85]
In the citing paper
“Both 2G and 3G EGFR‐TKI are irreversible small‐molecule inhibitors that covalently bind to EGFR kinase by targeting the cysteine‐797 residue, located in the ATP binding pocket, and 3G EGFR‐TKI are considered to be more specific for EGFR sensitizing mutations than 2G EGFR‐TKI.12, 13, 14”
In the citing paper
“Osimertinib and rociletinib are 3rd generation EGFR-TKIs, both of which are reported to be effective in lung cancer cells harboring EGFR T790M in preclinical models [30, 32].”
In the citing paper
“A third generation of EGFR inhibitors followed afatinib; these covalent inhibitors selectively target the T790M mutant over wild-type EGFR, and include WZ4002 (Dana–Farber Cancer Institute)43, osimertinib44,45 and rociletinib (Clovis Oncology; CO-1686)46 (Fig. 2c).”
From Advances in covalent drug discovery (2022) · cites this paper as [46]
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Metadata
- Authors
- Walter, A. O., Sjin, R. T. T., Haringsma, H. J., Ohashi, K., Sun, J., Lee, K., Dubrovskiy, A., Labenski, M., Zhu, Z., Wang, Z., Sheets, M., St Martin, T., Karp, R., van Kalken, D., Chaturvedi, P., Niu, D., Nacht, M., Petter, R. C., Westlin, W., Lin, K., Jaw-Tsai, S., Raponi, M., Van Dyke, T., Etter, J., Weaver, Z., Pao, W., Singh, J., Simmons, A. D., Harding, T. C., & Allen, A.
- Affiliations
- Vanderbilt University (US)
- Authors' Affiliations: 1Clovis Oncology Inc., San Francisco, California; 2Celgene Avilomics Research, Bedford, Massachusetts; 3Division of Hematology-Oncology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 4Mouse Cancer Genetics Program; and 5Center for Advanced Preclinical Research, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, Maryland
- Corresponding author
- Harding, Thomas C.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2013-12-01
- Volume
- 3
- Issue
- 12
- Pages
- 1404-1415
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4048995
- OpenAlex
- W2146418087
- Cited by
- 620
- References
- 43
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 21 · 2023: 29 · 2022: 32 · 2021: 41 · 2020: 51 · 2019: 44 · 2018: 61 · 2017: 87 · 2016: 92 · 2015: 86 · 2014: 44 · 2013: 3
- FWCI
- 62.72
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- other-oa
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HHSN261200800001C)
- National Cancer Institute (P30 CA 68485, R01CA121210, P01CA129243, HHSN261200800001E), U54CA143798, P30CA068485)
- 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 Mechanisms and Therapy
- Keywords
- EGFR tyrosine kinase inhibitors, T790M mutation, acquired drug resistance, non-small cell lung cancer, irreversible kinase inhibitors, epithelial-mesenchymal transition, AKT inhibitors, on-target toxicity
- MeSH terms
- Acrylamides, Administration, Oral, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Drug Screening Assays, Antitumor, Female, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Mice, Transgenic, Pyrimidines, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mutant Proteins, Mice, HEK293 Cells, Epithelial-Mesenchymal Transition, Molecular Targeted Therapy, ErbB Receptors
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