F-155 비소세포 폐암에서 Leucyl-tRNA 합성 효소 억제제인 B1206의 치료 효과

Among the aminoacyl-tRNA synthetases (ARSs), leucyl-tRNA synthetase (LRS) involves in amino acid-induced mTOR complex 1 (mTORC1) activation by sensing intracellular leucine concentration. Because mTORC1 regulates cell growth and proliferation, we hypothesized that inhibition of LRS inhibits cell growth and proliferation and synergize in cell death when combined with cytotoxic agents. Among 117 human NSCLC tissues, LRS was overexpressed in the 52 (44.4%) cases of cytoplasm and the expression of pS6 showed significant correlation with that of LRS expression. Treatment of B1206 inhibited phosphorylation of pp70S6K, pS6, and p4EBP1 in a dose dependent manner, whereas it did not influence phosphorylation of pAKT and pGSK. There was a significant change in the cell size by treatment of B1206, which suggesting B1206 possesses mTORC1 inhibitory effect. H2009, H460, and H358 cells were sensitive to B1206 and cell death occurred below 10 uM. In LSL-Kras G12D mouse model, treatment of B1206, cisplatin, and combination of both drugs significantly reduced tumor size when compared with that of vehicle treated group and the anti-tumor effect of B1206 and cisplatin was comparable. However, combination of B1206 and cisplatin did not show significant difference in tumor size when compared with single drug treatment. This study suggests that B1206 could be used as a new concept of therapy for NSCLC by inhibiting the non-canonical function of LRS and that continuous efforts are required on exploring non-canonical function of ARS as well as its inherent function for protein synthesis.