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

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Title: Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition
Authors: Nath, Kavindra, Gupta, Pradeep K., Basappa, Johnvesly, Wang, Shengchun, Sen, Neil, Lobello, Cosimo, Tomar, Jyoti S., Shestov, Alexander A., Orlovskiy, Stepan, Arias-Mendoza, Fernando, Rauert-Wunderlich, Hilka, Nelson, David S., Glickson, Jerry D., Wasik, Mariusz A.
Source: J Transl Med
Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-12 (2024)
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: 0301 basic medicine, Mantle cell lymphoma (MCL), Lymphoma, Mantle-Cell, Mice, 03 medical and health sciences, Cell Line, Tumor [MeSH], Lymphoma, Mantle-Cell/metabolism [MeSH], Xenograft Model Antitumor Assays [MeSH], Signal Transduction/drug effects [MeSH], Lymphoma, Mantle-Cell/pathology [MeSH], Signaling inhibition, Agammaglobulinaemia Tyrosine Kinase/metabolism [MeSH], Immunobiology and immunotherapy, Protein Kinase Inhibitors/pharmacology [MeSH], Humans [MeSH], ACP-196 (acalabrutinib), Proton magnetic resonance spectroscopy (, Animals [MeSH], Lymphoma, Mantle-Cell/drug therapy [MeSH], RNA Sequence analysis (RNA-Seq), Ibrutinib (IBR), Tricarboxylic or Citric acid cycle (TCA), Mice [MeSH], Biomarkers, Tumor/metabolism [MeSH], Magnetic resonance spectroscopy (MRS), Agammaglobulinaemia Tyrosine Kinase/antagonists, Research, Biomarkers/metabolism [MeSH], Bruton's tyrosine kinase (BTK), Cell Proliferation/drug effects [MeSH], Cell Line, Tumor, Agammaglobulinaemia Tyrosine Kinase, Biomarkers, Tumor, Humans, Animals, Protein Kinase Inhibitors, Cell Proliferation, Proton magnetic resonance spectroscopy (1H MRS), 0303 health sciences, Xenograft Model Antitumor Assays, 3. Good health, Medicine, Biomarkers, Signal Transduction
Description: 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 1H 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 1H 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.
Document Type: Article
Other literature type
Language: English
ISSN: 1479-5876
DOI: 10.1186/s12967-024-05371-9
Access URL: https://pubmed.ncbi.nlm.nih.gov/38965536
https://doaj.org/article/0e7806c50fd74e3da89b30454ab92a58
https://repository.publisso.de/resource/frl:6523258
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Accession Number: edsair.doi.dedup.....c0c406c087a4f976a1f6522ec4165e01
Database: OpenAIRE
Description
Abstract: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 1H 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 1H 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.
ISSN:14795876
DOI:10.1186/s12967-024-05371-9