| 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
|
| Resource |
| Human and Animal Cells |
Ba/F3(RCB0805)
II-18(RCB2093)
A431(RCB1872) |
