TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells

• Published in: PloS one Vol. 10; no. 6; p. e0129838
• Main Authors: Otani, Hiroki, Yamamoto, Hiromasa, Takaoka, Munenori, Sakaguchi, Masakiyo, Soh, Junichi, Jida, Masaru, Ueno, Tsuyoshi, Kubo, Takafumi, Asano, Hiroaki, Tsukuda, Kazunori, Kiura, Katsuyuki, Hatakeyama, Shinji, Kawahara, Eiji, Naomoto, Yoshio, Miyoshi, Shinichiro, Toyooka, Shinichi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.06.2015; Public Library of Science (PLoS)
• Subjects: Affinity; Analysis; Animal models; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; ATP; Binding; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Dentistry; Disease Models, Animal; Drug Resistance, Neoplasm; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Humans; Inhibition; Insulin; Insulin-like growth factors; Kinases; Laboratory animals; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical prognosis; Medicine; Mice; Morpholines - pharmacology; Mutation; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Pharmaceutical sciences; Phosphorylation; Protein Binding; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors - pharmacology; Proteins; Pyrimidines; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - chemistry; Receptor, Epidermal Growth Factor - genetics; Receptor, IGF Type 1 - metabolism; Small cell lung carcinoma; Surgery; Toxicity; Tumors; University graduates; Xenograft Model Antitumor Assays; Switzerland; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0129838

TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.