Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells

Lee, Seung‐Cheol; Shestov, Alexander A.; Guo, Lili; Zhang, Qian; Roman, Jeffrey; Liu, Xiaobin; Wang, Hong Y; Pickup, Stephen; Nath, Kavindra; Lü, Ping; Hofbauer, Samuel; Mesaros, Clementina; Wang, Y. Lynn; Nelson, David S.; Schuster, Stephen J.; Blair, Ian A.; Glickson, Jerry D.; Wasik, Mariusz A.

doi:10.1158/1541-7786.mcr-18-0256

Cited by 16 publications

(15 citation statements)

References 29 publications

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“…In contrast, ibrutinib-resistant MCL cells display increased OxPhos, and combining ibrutinib to IACS-010759 blocks tumor growth [ 375 ]. Ibrutinib resistance also correlates to higher glutaminolysis, that renders glutaminase inhibitor CB-839 efficient at killing ibrutinib-resistant MCL cells [ 429 ].…”

Section: Targeting Metabolic Reprogramming In B Cell Malignancies—pre...mentioning

confidence: 99%

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

Tannoury

Garnier

Susin

et al. 2022

Cancers

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Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today’s commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of inhibitors of anti-apoptotic proteins from the B-cell lymphoma/leukemia 2 family and the B-cell receptor (BCR) signaling pathway. Orally administered small-molecule inhibitors of Bcl-2 protein and BCR partners (e.g., Bruton’s tyrosine kinase and phosphatidylinositol-3 kinase) have already been included (as monotherapies or combination therapies) in the standard of care for selected B cell malignancies. Agonistic monoclonal antibodies and their derivatives (antibody–drug conjugates, antibody–radioisotope conjugates, bispecific T cell engagers, and chimeric antigen receptor-modified T cells) targeting tumor-associated antigens (TAAs, such as CD19, CD20, CD22, and CD38) are indicated for treatment (as monotherapies or combination therapies) of patients with B cell tumors. However, given that some patients are either refractory to current therapies or relapse after treatment, novel therapeutic strategies are needed. Here, we review current strategies for managing B cell malignancies, with a focus on the ongoing clinical development of more effective, selective drugs targeting these molecules, as well as other TAAs and signaling proteins. The observed impact of metabolic reprogramming on B cell pathophysiology highlights the promise of targeting metabolic checkpoints in the treatment of these disorders.

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Section: Targeting Metabolic Reprogramming In B Cell Malignancies—pre...mentioning

confidence: 99%

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

Tannoury

Garnier

Susin

et al. 2022

Cancers

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show abstract

“…The Bruton tyrosine kinase (BTK) inhibitor ibrutinib abolishes BCR signaling and has emerged as a potent therapeutic option for r/r MCL. BTK-blockade markedly affected the (ibrutinib-responsive) MCLs' metabolic activity including glycolysis and the TCA cycle (33). Interestingly, Zhang et al reported that ibrutinib-resistant MCLs depict a metatobolic rewiring toward glutaminolysis-fueled OxPhos (34).…”

Section: Mantle Cell Lymphoma (Mcl)mentioning

confidence: 99%

“…The most studied example of nutrient competition is the increased glucose consumption by malignant cells caused by elevated expression levels of glucose transporters and enzymes of the glycolytic machinery {as seen in BCR-DLBCL [e.g., GAPDH expression ( 52 ) and lactate secretion ( 13 )], transformed FL [e.g., GAPDH and aldolase A ( 27 , 28 )], MCL [e.g., glycolytic flux ( 33 )], and CLL in the LN-/BM-niche [e.g., glycolytic flux and key glycolytic enzymes ( 44 )]}. This is detrimental for T- and NK-cells as their proliferation, activation, and differentiation is highly dependent on glucose as a fuel for both aerobic glycolysis and OxPhos [reviewed in ( 53 )].…”

Section: Lymphoma Metabolism and Its Potential Impact On Anti-lymphommentioning

confidence: 99%

Linking Immunoevasion and Metabolic Reprogramming in B-Cell–Derived Lymphomas

et al. 2020

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Lymphomas represent a diverse group of malignancies that emerge from lymphocytes. Despite improvements in diagnosis and treatment of lymphomas of B-cell origin, relapsed and refractory disease represents an unmet clinical need. Therefore, it is of utmost importance to better understand the lymphomas' intrinsic features as well as the interactions with their cellular microenvironment for developing novel therapeutic strategies. In fact, the role of immune-based approaches is steadily increasing and involves amongst others the use of monoclonal antibodies against tumor antigens, inhibitors of immunological checkpoints, and even genetically modified T-cells. Metabolic reprogramming and immune escape both represent well established cancer hallmarks. Tumor metabolism as introduced by Otto Warburg in the early 20th century promotes survival, proliferation, and therapeutic resistance. Simultaneously, malignant cells employ a plethora of mechanisms to evade immune surveillance. Increasing evidence suggests that metabolic reprogramming does not only confer cell intrinsic growth and survival advantages to tumor cells but also impacts local as well as systemic anti-tumor immunity. Tumor and immune cells compete over nutrients such as carbohydrates or amino acids that are critical for the immune cell function. Moreover, skewed metabolic pathways in malignant cells can result in abundant production and release of bioactive metabolites such as lactic acid, kynurenine or reactive oxygen species (ROS) that affect immune cell fitness and function. This "metabolic re-modeling" of the tumor microenvironment shifts anti-tumor immune reactivity toward tolerance. Here, we will review molecular events leading to metabolic alterations in B-cell lymphomas and their impact on anti-tumor immunity.

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“…Recent investigations demonstrated that the genes involved in OXPHOS (e.g., ETC complexes I, III, IV, V) were largely dependent on MYC for translation (Singh et al 2019). Another line of evidence supports a role for glutamine-dependent OXPHOS as a mediator of ibrutinib resistance in mantle cell lymphoma (MCL), potentially driven by MYC and TOR activity (Lee et al 2019;Zhang et al 2019a). Ibrutinib-resistant MCL was uniquely dependent on glutamine uptake and glutaminolysis; disruption of glutamine metabolism or ETC complex I increased ROS, induced energetic stress, and overcame resistance to ibrutinib.…”

Section: Oxidative Phosphorylationmentioning

confidence: 99%

Oncogenic Mechanisms and Therapeutic Targeting of Metabolism in Leukemia and Lymphoma

Stahl

Epstein‐Peterson

Intlekofer

2020

Cold Spring Harb Perspect Med

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Leukemias and lymphomas acquire the capacity for unrestrained cell growth and proliferation in conjunction with loss of responsiveness to molecular programs that promote terminal differentiation. Malignant cells generate the building blocks required for rapid cell division through both increased acquisition of nutrients from the environment and reprogrammed intermediary metabolism to shunt these molecules into producing the protein, lipids, and nucleic acids that comprise cell biomass. These accelerated metabolic processes require energy in the form of ATP and reducing equivalents in the form of NADPH, which power biosynthetic reactions and buffer oxidative stress encountered by the metabolically active cancer cell. Cancer-associated metabolic alterations can also promote accumulation or depletion of specific metabolites that directly regulate cell fate and function, thereby coupling metabolic reprogramming to dedifferentiation and stemness. This review will focus on the mechanisms by which leukemia and lymphoma cells rewire cellular metabolism to support:(1) bioenergetics, (2) biomass accumulation, (3) redox balance, and (4) differentiation blockade. We will further highlight examples of how specific pathways of leukemia and lymphoma metabolism confer therapeutic vulnerabilities that can be targeted to inhibit growth or promote differentiation.A t a fundamental level, cancer is a problem of hijacked cellular metabolism (Vander Heiden et al. 2009). Normally, metazoan cells require "permission" from growth factors, cytokines, hormones, or antigen/costimulatory receptors to increase nutrient uptake. All cancers, including leukemias and lymphomas, acquire the capacity for cell-autonomous uptake of nutrients that circumvents normal regulatory mechanisms (Palm and Thompson 2017). Such unrestricted nutrient uptake is critical to build the cellular biomass ( protein, lipids, nucleic acids) necessary for rapid cell doubling (Fig. 1). Because the availability of specific nutrients in the environment does not precisely match the necessary outputs, cancer cells must rewire metabolic circuits to rapidly convert available nutrients into precursor metabolites

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Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells

Cited by 16 publications

References 29 publications

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

Linking Immunoevasion and Metabolic Reprogramming in B-Cell–Derived Lymphomas

Oncogenic Mechanisms and Therapeutic Targeting of Metabolism in Leukemia and Lymphoma

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