Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

Walter, Annette O.; Sjin, Robert Tjin Tham; Haringsma, Henry J.; Ohashi, Kadoaki; Sun, Jing; Lee, Kwangho; Dubrovskiy, Aleksandr; Labenski, Matthew; Zhu, Zhendong; Wang, Zhigang; Sheets, Michael; St Martin, Thia; Karp, Russell; van Kalken, Dan; Chaturvedi, Prasoon; Niu, Deqiang; Nacht, Mariana; Petter, Russell C.; Westlin, William; Lin, Kevin; Jaw-Tsai, Sarah; Raponi, Mitch; Van Dyke, Terry; Etter, Jeff; Weaver, Zoe; Pao, William; Singh, Juswinder; Simmons, Andrew D.; Harding, Thomas C.; Allen, Andrew

doi:10.1158/2159-8290.cd-13-0314

Cited by 686Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Mechanisms and Therapy

Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

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Walter, Annette O., Sjin, Robert Tjin Tham, Haringsma, Henry J., Ohashi, Kadoaki, Sun, Jing, Lee, Kwangho, Dubrovskiy, Aleksandr, Labenski, Matthew +22 more·2013·Cancer Discovery

DOI 10.1158/2159-8290.cd-13-0314PMC PMC4048995

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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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Rociletinib is a specific mutant agent for the treatment of NSCLC, belonging to the third-generation EGFR TKIs, developed by Clovis Oncology.
“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]
Covalent inhibitors can exhibit high selectivity for proteins with non-conserved residues between variant forms or protein family members.
“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]
AZD9291 has a chemical structure distinct from WZ4002 and CO-1686.
“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]
Pre-clinical reports suggest that third-generation agents can induce switching to multiple signaling mechanisms that bypass EGFR dependency, including ERK and AKT pathways.
“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]
Preclinical studies have shown that rociletinib has minimal activity against wild-type EGFR.
“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]

Rociletinib is an EGFR inhibitor that is active in preclinical models of EGFR-mutated non-small-cell lung cancer, both with and without the T790M mutation.
“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]
Xenograft models carrying EGFR-activating mutations, with or without T790M, showed durable tumor shrinkage with rociletinib, greatest when plasma levels stayed above 200 ng/mL.
“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]
Rociletinib is an orally available small molecule that covalently and selectively inhibits common EGFR mutations such as exon 19 deletions, L858R, and T790M, but not exon 20 insertions.
“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]
EGFR monoclonal antibodies and EGFR WT kinase sparing covalent T790M selective TKIs are ineffective in typical EGFR exon 20 insertion mutants.
“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]
Cysteine 797 is the site of covalent binding for WZ4002, CO-1686, and AZD9291.
“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]
The irreversible pyrimidine EGFR inhibitors WZ4002, CO-1686, and AZD9291 are more potent against T790M and selectively inhibit mutant over wild-type EGFR, which should improve efficacy and reduce toxicity compared with afatinib.
“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]
Mutant-selective EGFR kinase inhibitors including WZ4002, CO-1686, and AZD9291 have demonstrated encouraging efficacy in preclinical models and in EGFR mutant NSCLC patients with EGFR T790M-mediated drug resistance.
“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]
CO-1686 is structurally more closely related to WZ4002 than to AZD9291, and in all models tested CO-1686 is very similar in vitro to WZ4002.
“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]
Additional preclinical studies have identified activation of MAPK signaling, IGF1R signaling, and epithelial-to-mesenchymal transition as potential resistance mechanisms to WZ4002 and CO-1686.
“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]
Rociletinib irreversibly and selectively inhibits mutant EGFR, including T790M mutation, with minimal activity against wild type EGFR, suggesting that drug tolerability may be superior to first and second generation EGFR inhibitors.
“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]
Both 2G and 3G EGFR-TKIs are irreversible small-molecule inhibitors that covalently bind to EGFR kinase by targeting cysteine-797 in the ATP binding pocket, and 3G EGFR-TKIs are considered more specific for EGFR sensitizing mutations than 2G EGFR-TKIs.
“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”
From Sensitivities to various epidermal growth factor receptor‐tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor‐tyrosine kinase inhibitor? (2016) · cites this paper as [13]
Osimertinib and rociletinib are effective in lung cancer cells harboring EGFR T790M in preclinical models.
“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].”
From In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer (2015) · cites this paper as [32]
Third-generation EGFR inhibitors selectively target T790M over wild-type EGFR, including osimertinib.
“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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AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
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Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models
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Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer
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Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors
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Glioblastoma Therapy: Past, Present and Future
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The Cysteinome of Protein Kinases as a Target in Drug Development
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Mechanisms of Acquired Resistance to AZD9291
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“A recent study has found that a low level of PTEN expression does not necessarily signify high activity of AKT, and that areas with different levels of AKT activation co-exist within the same adenocarcinoma of lung [165].”
BackgroundInfluential
Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC)
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Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC
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Drug resistance to targeted therapies: Déjà vu all over again
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The Ascension of Targeted Covalent Inhibitors
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EMT: A mechanism for escape from EGFR-targeted therapy in lung cancer
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NF-κB-Activating Complex Engaged in Response to EGFR Oncogene Inhibition Drives Tumor Cell Survival and Residual Disease in Lung Cancer
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Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer
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Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines
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SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer
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Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer
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A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib
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Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer
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RESEARCH ARTICLE OF1 | CANCER DISCOVERYDECEMBER 2013 www.aacrjournals.org Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M- Mediated Resistance in NSCLC
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Self-citation
Abstract B120: Preclinical assessment of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.
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Abstract 1791: CO-1686, a novel mutant-selective EGFR inhibitor, overcomes T790M mediated resistance in Non-Small Cell Lung Cancer (NSCLC)
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Abstract C189: CO-1686, an orally available, mutant-selective inhibitor of the epidermal growth factor receptor (EGFR), causes tumor shrinkage in non-small cell lung cancer (NSCLC) with T790M mutations.
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Structural basis of mutant-selectivity and drug-resistance related to CO-1686
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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: Sjin, Robert Tjin Tham
Ohashi, Kadoaki
Sun, Jing
Lee, Kwangho
Zhu, Zhendong
Wang, Zhigang
Karp, Russell
Chaturvedi, Prasoon
Westlin, William
Lin, Kevin
Raponi, Mitch
Pao, William
Singh, Juswinder
Simmons, Andrew D.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2013-12-01
Volume: 3
Issue: 12
Pages: 1404-1415
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-13-0314
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
Health Sciences › Medicine › Pathology and Forensic Medicine › 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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Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

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