Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

Autor: Nath K; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA. kavindra.nath@pennmedicine.upenn.edu., Gupta PK; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA., Basappa J; Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA., Wang S; Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA., Sen N; Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA., Lobello C; Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA., Tomar JS; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA., Shestov AA; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA., Orlovskiy S; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA., Arias-Mendoza F; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.; Advanced Imaging Research, Inc., Cleveland, OH, USA., Rauert-Wunderlich H; Institute of Pathology, University of Würzburg, Würzburg, Germany., Nelson DS; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA., Glickson JD; Department of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA., Wasik MA; Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA. mariusz.wasik@fccc.edu.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 Jul 04; Vol. 22 (1), pp. 622. Date of Electronic Publication: 2024 Jul 04.
DOI: 10.1186/s12967-024-05371-9
Abstrakt: Background: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1 H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition.
Methods: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1 H MRS.
Results: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth.
Conclusions: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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