Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations, T790M Mutation, and AXL Overexpression
Published version of a preprint
Abstract
Abstract First- and second-generation EGFR tyrosine kinase inhibitors (TKI) are effective clinical therapies for patients with non–small cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, almost all patients develop resistance to these drugs. The EGFR T790M mutation of EGFR is the most predominant mechanism for resistance. In addition, activation of AXL signaling is one of the suggested alternative bypassing pathways for resistance to EGFR-TKIs. Here, we report that naquotinib, a pyrazine carboxamide–based EGFR-TKI, inhibited EGFR with activating mutations, as well as T790M resistance mutation while sparing wild-type (WT) EGFR. In in vivo murine xenograft models using cell lines and a patient-derived xenograft model, naquotinib induced tumor regression of NSCLC with EGFR-activating mutations with or without T790M resistance mutation, whereas it did not significantly inhibit WT EGFR signaling in skin. Furthermore, naquotinib suppressed tumor recurrence during the treatment period of 90 days. In addition, unlike erlotinib and osimertinib, naquotinib inhibited the phosphorylation of AXL and showed antitumor activity against PC-9 cells overexpressing AXL in vitro and in vivo. Our findings suggest that naquotinib has therapeutic potential in patients with NSCLC with EGFR-activating mutations, T790M resistance mutation, and AXL overexpression.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Naquotinib is active against EGFR mutant cell lines resistant to other EGFR TKIs such as AZD9291 and CO-1686.
“Naquotinib also inhibits signaling pathways through ERK and Akt, and is active against EGFR mutant cell lines resistant to other EGFR TKIs such as AZD9291 and CO-1686.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [195]
Cites
Sequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228 · see citing works
Bean, J., Brennan, C., Shih, J.-Y., Riely, G., Viale, A., Wang, L., Chitale, D., Motoi, N., Szoke, J., Broderick, S., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710370104 · Cited by 1,598 · see citing works
Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., LaFramboise, T., Abdel-Rahman, M., Wang, X., Levine, A. D., Rho, J. K., et al. (2012) · Nature Genetics · doi:10.1038/ng.2330 · Cited by 1,224 · see citing works
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., et al. (2009) · Nature · doi:10.1038/nature08622 · Cited by 1,013 · see citing works
Rociletinib in <i>EGFR</i>-Mutated Non–Small-Cell Lung Cancer
Sequist, L. V., Soria, J.-C., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Papadimitrakopoulou, V., Solomon, B. J., Oxnard, G. R., Dziadziuszko, R., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1413654 · Cited by 665 · see citing works
Walter, A. O., Sjin, R. T. T., Haringsma, H. J., Ohashi, K., Sun, J., Lee, K., Dubrovskiy, A., Labenski, M., Zhu, Z., Wang, Z., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0314 · Cited by 620 · see citing works
Gjerdrum, C., Tiron, C., Høiby, T., Stefansson, I., Haugen, H., Sandal, T., Collett, K., Li, S., McCormack, E., Gjertsen, B. T., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909333107 · Cited by 594 · see citing works
Blakely, C. M., & Bivona, T. G. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0387 · Cited by 39 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
- Authors
- Tanaka, H., Sakagami, H., Kaneko, N., Konagai, S., Yamamoto, H., Matsuya, T., Yuri, M., Yamanaka, Y., Mori, M., Takeuchi, M., Koshio, H., Hirano, M., & Kuromitsu, S.
- Affiliations
- Astellas Pharma (Japan) (JP)
- Venue
- Molecular Cancer Therapeutics
- Published
- 2019-08-01
- Volume
- 18
- Issue
- 8
- Pages
- 1366-1373
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2946302039
- Cited by
- 18
- References
- 8
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 3
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Astellas PharmaAstellas Pharma (Astellas)
- 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 Genomics and Diagnostics
- Keywords
- EGFR tyrosine kinase inhibitors, non-small cell lung cancer, EGFR activating mutations, T790M mutation, drug resistance, patient-derived xenografts, tumor recurrence, erlotinib, osimertinib, PC9 cells
- MeSH terms
- Axl Receptor Tyrosine Kinase, Animals, Carcinoma, Non-Small-Cell Lung, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Lung Neoplasms, Mutation, Piperazines, Piperidines, Proto-Oncogene Proteins, Pyrazines, Pyrrolidines, Signal Transduction, Gene Expression Regulation, Neoplastic, Receptor Protein-Tyrosine Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, 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 ›
Are you an author, or do you see a problem with this page? Request a review
