Reference - Detail
| RRC ID | 59712 |
|---|---|
| Author | 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. |
| Title | Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations, T790M Mutation, and AXL Overexpression. |
| Journal | Mol Cancer Ther |
| 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. |
| Volume | 18(8) |
| Pages | 1366-1373 |
| Published | 2019-8-1 |
| DOI | 10.1158/1535-7163.MCT-18-0976 |
| PII | 1535-7163.MCT-18-0976 |
| PMID | 31092564 |
| MeSH | Animals Axl Receptor Tyrosine Kinase Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics* Carcinoma, Non-Small-Cell Lung / metabolism* Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Disease Models, Animal Dose-Response Relationship, Drug ErbB Receptors / genetics ErbB Receptors / metabolism Gene Expression Regulation, Neoplastic / drug effects Humans Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Lung Neoplasms / metabolism* Lung Neoplasms / pathology Mice Mutation* Piperazines / pharmacology* Piperidines / pharmacology* Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins / metabolism Pyrazines / pharmacology* Pyrrolidines / pharmacology* Receptor Protein-Tyrosine Kinases / genetics* Receptor Protein-Tyrosine Kinases / metabolism Signal Transduction / drug effects Xenograft Model Antitumor Assays |
| IF | 4.856 |
| Times Cited | 4 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | Ba/F3(RCB0805) II-18(RCB2093) A431(RCB1872) |