ABSTRACT
Purpose@#The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and proliferation by growth factor coordination and amino acid availability. Leucyl-tRNA synthetase 1 (LARS1) senses the intracellular leucine concentration and mediates amino acid-induced activation of mTORC1. Thus, LARS1 inhibition could be useful in cancer treatment. However, the fact that mTORC1 can be stimulated by various growth factors and amino acids suggests that LARS1 inhibition alone has limitations in inhibiting cell growth and proliferation. We investigated the combined effects of BC-LI-0186, a LARS1 inhibitor, and trametinib, an MEK inhibitor, on non–small cell lung cancer (NSCLC). @*Materials and Methods@#Protein expression and phosphorylation were observed by immunoblotting, and genes differentially expressed between BC-LI-0186–sensitive and –resistant cells were identified by RNA sequencing. The combined effect of the two drugs was inferred from the combination index values and a xenograft model. @*Results@#LARS1 expression was positively correlated with mTORC1 in NSCLC cell lines. BC-LI-0186 treatment of A549 and H460 cells maintained in media supplemented with fetal bovine serum revealed paradoxical phosphorylation of S6 and activation of mitogen- activated protein kinase (MAPK) signaling. Compared with BC-LI-0186–sensitive cells, –resistant cells showed enrichment of the MAPK gene set. The combination of trametinib and BC-LI-0186 inhibited the phosphorylation of S6, MEK, and extracellular signal-regulated kinase and their synergistic effects were confirmed in a mouse xenograft model. @*Conclusion@#The combination of BC-LI-0186 and trametinib inhibited the non-canonical mTORC1-activating function of LARS1. Our study demonstrated a new therapeutic approach for NSCLC without targetable driver mutations.
ABSTRACT
OBJECTIVE: Biomarkers of attention deficit hyperactivity disorder (ADHD) are crucial for early diagnosis and intervention, in which the identification of biomarkers in other areas of the body that represent the immature brain of children with ADHD is necessary. The present study aimed to find biomarkers of ADHD in the retina and assessed the relationship between macular thickness of the retina and cortical thickness of the brain in children with ADHD. METHODS: Twelve children with ADHD and 13 control children were recruited for the study. To find ocular markers of ADHD, we investigated the correlation between clinical symptoms of ADHD assessed with the Korean ADHD Rating Scale (K-ARS), cortical thickness of the brain, and macular thickness measured with the mean thickness from the Early Treatment Diabetic Retinopathy Study (ETDRS). RESULTS: Children with ADHD showed increased macular thicknesses quantified as an ETDRS ring in both eyes, compared to control subjects. Moreover, the right inner ETDRS ring had a positive correlation with K-ARS scores. The ADHD group had an increased ratio of thickness of the right frontal lobe to that of the parietal cortex, compared with the control group. There were positive correlations between the means of the inner ETDRS ring (right) and the left paracentral/right isthmus cingulate thicknesses in the control group. However, there were negative correlations between the means of the inner ETDRS ring (right) and the left frontal pole/right pars triangularis thicknesses in the ADHD group. The results of both groups were at the uncorrected level. CONCLUSION: The different patterns of macular thickness might represent the immature cortical thickness of the brain in children with ADHD.