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.

Hiroki Otani,Tsuyoshi Ueno,Eiji Kawahara,Yoshio Naomoto,Katsuyuki Kiura,Hiroaki Asano,Shinichi Toyooka,Munenori Takaoka,Masakiyo Sakaguchi,Kazunori Tsukuda,Shinichiro Miyoshi,Takafumi Kubo,Hiromasa Yamamoto,Masaru Jida,Junichi Soh,Shinji Hatakeyama

doi:10.1371/journal.pone.0129838

Hiroki Otani, Tsuyoshi Ueno + Show 14 more

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https://doi.org/10.1371/journal.pone.0129838

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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.

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Lung cancer is the leading cause of cancer death worldwide [1]
4-anilinoquinazoline inhibitors, such as gefitinib and erlotinib, have been designed to inhibit the tyrosine kinase domain of epidermal growth factor receptor (EGFR), which is overexpressed in non-small-cell lung cancer (NSCLC); such inhibitors are currently being used for the treatment of NSCLC [5,6,7,8]
The inhibitory concentration at 50% (IC50) values for EGFR wild-type NSCLC cell lines (n = 10: ranged from 0.28 to 6.2 μM) were higher than those of EGFR-mutant NSCLC cell lines two BRAF mutant cell lines and one EML4-ALK translocated cell line showed intermediate level of IC50 values. These results suggested that TAE226 was more effective in EGFR-mutant cell lines, regardless of the presence of the TKI-resistant EGFR T790M mutation, than in EGFR wild-type cell lines, especially which did not have BRAF or EML4-ALK alterations

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Introduction

Lung cancer is the leading cause of cancer death worldwide [1]. Lung cancer is divided into two major histological categories, non-small-cell lung cancer (NSCLC) and small-cell lung cancer. 4-anilinoquinazoline inhibitors, such as gefitinib and erlotinib, have been designed to inhibit the tyrosine kinase domain of epidermal growth factor receptor (EGFR), which is overexpressed in NSCLC; such inhibitors are currently being used for the treatment of NSCLC [5,6,7,8]. Of particular interest, these EGFR tyrosine kinase inhibitors (EGFR-TKIs) produce drastic anti-tumor effects against NSCLCs carrying common EGFR mutations, small deletions at exon 19 and L858R mutation at exon 21. T790M mutations are found in approximately 50% cases among NSCLCs that acquired resistance to EGFR-TKI [16]

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