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Combination of the LARS1 Inhibitor, BC-LI-0186 with a MEK1/2 Inhibitor Enhances the Anti-Tumor Effect in Non-Small Cell Lung Cancer

Authors
 Sang Hoon Lee  ;  Eun Young Kim  ;  Jung Min Han  ;  Gyoonhee Han  ;  Yoon Soo Chang 
Citation
 CANCER RESEARCH AND TREATMENT, Vol.55(3) : 851-864, 2023-06 
Journal Title
CANCER RESEARCH AND TREATMENT
ISSN
 1598-2998 
Issue Date
2023-06
MeSH
Amino Acids / pharmacology ; Amino Acids / therapeutic use ; Animals ; Carcinoma, Non-Small-Cell Lung* / drug therapy ; Carcinoma, Non-Small-Cell Lung* / genetics ; Carcinoma, Non-Small-Cell Lung* / pathology ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Mammals / metabolism ; Mechanistic Target of Rapamycin Complex 1 / metabolism ; Mechanistic Target of Rapamycin Complex 1 / pharmacology ; Mice ; Mitogen-Activated Protein Kinase Kinases / pharmacology ; Mitogen-Activated Protein Kinase Kinases / therapeutic use ; Protein Kinase Inhibitors / therapeutic use
Keywords
BC-LI-0186 ; LARS1 ; Non-small cell lung cancer ; Trametinib ; mTORC1
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.
Files in This Item:
T202303868.pdf Download
DOI
10.4143/crt.2022.1527
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eun Young(김은영) ORCID logo https://orcid.org/0000-0002-3281-5744
Lee, Sang Hoon(이상훈) ORCID logo https://orcid.org/0000-0002-7706-5318
Chang, Yoon Soo(장윤수) ORCID logo https://orcid.org/0000-0003-3340-4223
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/195578
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