Abstract
Current methods to evaluate effects of kinase inhibitors in cancer are suboptimal. Analysis of changes in cancer metabolism in response to the inhibitors creates an opportunity for better understanding of the interplay between cell signaling and metabolism and, from the translational perspective, potential early evaluation of response to the inhibitors as well as treatment optimization. We performed genomic, metabolomic, and fluxomic analyses to evaluate the mechanism of action of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (IBR) in mantle cell lymphoma (MCL) cells. Our comprehensive analysis of the data generated by these diverse technologies revealed that IBR profoundly affected key metabolic pathways in IBR-sensitive cells including glycolysis, pentose phosphate pathway, TCA cycle, and glutaminolysis while having much less effects on IBR-poorly responsive cells. Changes in 1H magnetic resonance spectroscopy (MRS)-detectable lactate and alanine concentrations emerged as promising biomarkers of response and resistance to IBR as demonstrated from experiments on various MCL cell lines. The metabolic network analysis on the 13C MRS and 13C LC/MS experimental data provided quantitative estimates of various intracellular fluxes and energy contributions. Glutaminolysis contributed over 50% of mitochondrial ATP production. Administration of the glutaminase inhibitor CB-839 induced growth suppression of the IBR-poorly responsive cells. IMPLICATIONS: Our study demonstrates application of the advanced metabolomic/fluxomic techniques for comprehensive, precise, and prompt evaluations of the effects of kinase inhibition in MCL cells and has strong translational implications by potentially permitting early evaluation of cancer patient response versus resistance to kinase inhibitors and on design of novel therapies for overcoming the resistance.