Targeting glucose and glutamine metabolism combined with radiation therapy in non-small cell lung cancer.

Highlights • NSCLC cell lines respond different to glycolysis and/or glutaminase inhibition. • KRAS mutation and glutaminase C expression predict response to treatment. • Only a part of NSCLC cell lines are radiosensitized by metabolic inhibition. • So, NSCLC is a heterogeneous disease, making stratification necessary. Abstract Purpose Metabolic inhibition might sensitize tumors to irradiation. Here, we examined the effect of lonidamine (several metabolic effects, inhibiting hexokinase amongst others) and/or 968 (glutaminase inhibitor) on tumor cell metabolism, cell growth, cytotoxicity and radiosensitivity in NSCLC cell lines in vitro in relation to histology. Materials and methods Adeno- (H23, HCC827, H1975) and squamous cell carcinoma (H520, H292, SW900) NSCLC cells were treated with lonidamine and/or 968 for 72 h under physiological levels of glucose (1.5 mM). Cells were irradiated with 0, 4 or 8 Gy. Cell growth of H2B-mCherry transduced cells and cytotoxicity (CellTox™ Green Cytotoxicity Assay) were measured using live cell imaging (IncuCyte). Inhibitory effects on metabolic profiles was determined using the Seahorse XF96 extracellular Flux analyzer. Results NSCLC cell lines responded differently to glycolysis (lonidamine) and/or glutaminase (968) inhibition, largely corresponding with changes in glycolytic and mitochondrial metabolism upon treatment. Response patterns were not related to histology. 968 was cytotoxic in cell lines with high glutaminase C expression (H1975 and H520), whereas combination treatment was cytotoxic in KRAS mutated cell lines SW900 and H23. H292 and HCC827 were resistant to combination treatment. Treatment with 968 and especially lonidamine resulted in radiosensitization of H292 and HCC827 in terms of decreased relative cell growth and increased cytotoxicity. Conclusion NSCLC is a heterogeneous disease, which is reflected in the response of different cell lines to the treatment (combinations) reported here. Only a part of NSCLC patients may benefit from the combination of radiation therapy and metabolic inhibition, making stratification necessary. [ABSTRACT FROM AUTHOR]