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TAE226, a bis-anilino pyrimidine compound, inhibits the EGFR-mutant kinase including T790M mutant to show anti-tumor effect on EGFR-mutant lung cancer cells

Otani, Hiroki and Yamamoto, Hiromasa and Takaoka, Munenori and Sakaguchi, Masakiyo and Soh, Junichi and Jida, Masaru and Ueno, Tsuyoshi and Kubo, Takafumi and Asano, Hiroaki and Tsukuda, Kazunori and Kiura, Katsuyuki and Hatakeyama, Shinji and Kawahara, Eiji and Huh, Nam-ho and Naomoto, Yoshio and Miyoshi, Shinichiro and Toyooka, Shinichi (2015) TAE226, a bis-anilino pyrimidine compound, inhibits the EGFR-mutant kinase including T790M mutant to show anti-tumor effect on EGFR-mutant lung cancer cells. PLoS One.

Abstract

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. 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.

Item Type: Article
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23188

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