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T. Kubo

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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.02 - TAE226, a Bis-Anilino Pyrimidine Compound, Shows Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells including T790M Mutant (ID 1646)

      10:45 - 12:15  |  Author(s): T. Kubo

      • Abstract
      • Presentation
      • Slides

      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). These tyrosine kinases are known to be overexpressed in many malignant tumors including some NSCLCs and to play an oncogenic role in cancer cells.

      We investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. Drug sensitivity of TAE226 to various NSCLC cell lines was determined by MTS assay. Interaction of TAE226 and variant EGFR proteins was evaluated by in vitro binding assay, and kinetic interaction analysis to calculate K~d~ value. Finally, the effect of TAE226 on NSCLC was investigated using a xenograft mouse model.

      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.

      We showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation. Our results showed that the EGFR L858R/T790M (or delE746_A750/T790M) mutant retains the binding affinity to TAE226 comparable to that of the L858R (or delE746_A750) mutant, suggesting that TAE226, or its relatives, is promising to overcome acquired TKI resistance mediated by EGFR T790M mutation.

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