Author of

• 20152

  +

  P1.03 - Chemotherapy/Targeted Therapy (ID 689)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Chemotherapy/Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 22589

    +

    P1.03-034 - Therapeutic Effect of Novel Leucyl-tRNA Synthetase Inhibitor, B1206, in Non-Small Cell Lung Cancer (ID 9270)

    09:30 - 09:30  |  Presenting Author(s): Eun Young Kim
    • Abstract

    Background:
    Among the aminoacyl-tRNA synthetases (ARSs) which catalyze ligation of amino acids to their cognate tRNAs, leucyl-tRNA synthetase (LRS) involves in amino acid-induced mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation by sensing intracellular leucine concentration. Because mTORC1 regulates cell growth and proliferation by coordination upstream signals such as growth factor and amino acid availability, we hypothesized that inhibition of LRS inhibits cell growth and proliferation and synergize in cell death when combined with cytotoxic agents.
    
    Method:
    Expression of LRS and pS6 was observed by immunochemical staining of NSCLC tissue from 117 patients. The effect of B1206 on mTORC1 signaling was analyzed by immunoblotting and confocal imaging and its cytotoxic effect was measured by flow cytometer after annexin V-propidium iodide staining. In vivo effect of B1206 was evaluated by microCT in LSL-Kras G12D mouse lung cancer model.
    
    Result:
    Among 117 human NSCLC tissues, LRS was overexpressed in the 52 (44.4%) cases of cytoplasm and 14 cases (11.2%) of nucleus and the expression of pS6(Ser235/236) in the serial tissue section from matched lung cancer patient showed significant correlation with that of LRS expression (Pearson’s correlation coefficiency=0.315, p-value<0.001). Treatment of B1206 inhibited phosphorylation of pp70S6K(T389), pS6(S235/236), and p4EBP1(T36/45) in a dose dependent manner, which is more prominent in 6 Hr after treatment. On the other hand, it did not influence phosphorylation of pAKT(S473) and pGSK(S9), which are signaling markers of mTORC2. There was a significant change in the cell size by treatment of sublethal dose of B1206, which is additional finding suggesting B1206 possesses mTORC1 inhibitory effect. Among the 10 cell lines tested, B1206 treatment could not induce cell death in 6 cell lines up to 30 uM of concentration. But H2009, H460, and H358 cells were sensitive to B1206 and most cell death occurred at concentrations below 10 uM and H1703 showed moderate sensitivity to B1206. 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.
    
    Conclusion:
    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.