AB060. Could glucose uptake ability enhanced by drugs result in antitumor effect in small cell lung cancer?

Objective: Leucyl-tRNA synthetase (LRS) is an aminoacyl-tRNA synthetase catalyzing ligation of leucine to its cognate tRNA and is involved in the activation of mTORC1 by sensing cytoplasmic leucine. In this study, the usefulness of LRS as a therapeutic target of non-small cell lung cancer (NSCLC) and the anticancer effect of the LRS inhibitor, BC-LI-0186, was evaluated. Methods: LRS expression and the antitumor effect of BC-LI-0186 were evaluated by immunohistochemical staining, immunoblotting, and live cell imaging. The in vivo antitumor effect of BC-LI-0186 was evaluated using Lox-Stop-Lox (LSL) K-ras G12D mice. Results: LRS was frequently overexpressed in NSCLC tissues, and its expression was positively correlated with mTORC1 activity. The guanosine-5’-triphosphate (GTP) binding status of RagB was related to the expression of LRS and the S6K phosphorylation. siRNA against LRS inhibited leucine-mediated mTORC1 activation and cell growth. BC-LI-0186 selectively inhibited phosphorylation of S6K without affecting phosphorylation of AKT and leucine-mediated co-localization of Raptor and LAMP2 in the lysosome. BC-LI-0186 induced cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3 and increase of p62 expression, showing that it has the autophagy-inducing property. BC-LI-0186 has the cytotoxic effect at nanomolar concentration and its GI50 value was negatively correlated with the degree of LRS expression. BC-LI-0186 showed the antitumor effect, which was comparable with that of cisplatin, and mTORC1 inhibitory effect in a lung cancer model. Conclusions: BC-LI-0186 inhibits the noncanonical mTORC1-activating function of LRS. These results provide a new therapeutic strategy for NSCLC and warrant future clinical development by targeting LRS.

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Abstract 6648: Racotumomab and PD-1 blockade combination exhibits an additive antitumor effect in a non-small cell lung cancer model

10.1158/1538-7445.am2020-6648 ◽

2020 ◽

Author(s):

Valeria I. Segatori ◽

Cynthia A. Gulino ◽

Carla S. Capobianco ◽

Selene Rojo ◽

Gretel M. Ferreira ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Antitumor Effect ◽

Small Cell ◽

Cancer Model ◽

Small Cell Lung ◽

Lung Cancer Model

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Antitumor effect of Chinese herb oridonin on human non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13526 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13526-e13526

Author(s):

Siyu Chen ◽

Wei Tian ◽

Ai-Hong Ma ◽

Sonal Desai ◽

Krysteena Tolentino ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Antitumor Effect ◽

Chinese Herb ◽

Small Cell ◽

Nsclc Cell ◽

Potential Drug ◽

Small Cell Lung

e13526 Background: Oridonin, a diterpenoid purified from the Chinese herb Rabdosia rubescens, has anti-inflammatory and potentially anti-tumor property. We aimed to study the antitumor effect of oridonin on a panel of human non-small cell lung cancer (NSCLC) cell lines. Methods: Human NSCLC cell lines with a wild-type EGFR gene and a RAS gene mutation were treated with escalating dose concentration of oridonin (from 2.5 to 50 µM). Antitumor effect was measured by 72-hr growth inhibition by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell morphology was observed under microscope. Ongoing experiments will identify potential drug target(s) by assessing changes in global gene expression. Results: Oridonin exhibited a dose-dependent and time-dependent cytotoxic effect on a panel of NSCLC cell lines. Table 1 summarizes the molecular and histological features of these NSCLC cells, and their cytotoxicity to oridinin, erlotinib and pemetrexed. In those NSCLC cells that were sensitive to oridonin, morphological changes were consistent with autophagy and apoptosis. Potential drug targets will be verified by RT-PCR and immunoblotting. Conclusions: Oridonin exerts a distinct cytotoxicity that is independent of the sensitivity of NSCLC cells to erlotinib or pemetrexed. Further mechanistic and animal studies are warranted to understand its anti-tumor property and toxicity profile in preclinical evaluation. [Table: see text]

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