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