Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway

Chen, Yan; Huang, Ruibin; Ding, Jianghua; Ji, Dexiang; Song, Bing; Lu, Yuan; Chang, Hong; Chen, Guoan

doi:10.1038/srep09925

Cited by 28 publications

(41 citation statements)

References 33 publications

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“…We showed that OCR, an indicator of oxidative phosphorylation, was suppressed following METi in METi-sensitive M1268T cells. This observation is in line with previously reported modulations of cellular metabolism by EGFR signaling, where Makinoshima et al documented changes in OCR in EGFR-inhibitor-treated lung adenocarcinoma cell line HCC827 and similar result was recapitulated by Chen et al in myeloma cells treated with the specific EGFR inhibitor gefitinib [38,39]. The OCR drop in M1268T cells might be caused by impairment of mitochondrial function via mitochondrial membrane depolarization following tepotinib administration, which was previously reported using other tyrosine kinase inhibitors.…”

Section: Discussionsupporting

confidence: 90%

“…documented changes in OCR in EGFR‐inhibitor‐treated lung adenocarcinoma cell line HCC827 and similar result was recapitulated by Chen et al . in myeloma cells treated with the specific EGFR inhibitor gefitinib . The OCR drop in M1268T cells might be caused by impairment of mitochondrial function via mitochondrial membrane depolarization following tepotinib administration, which was previously reported using other tyrosine kinase inhibitors.…”

Section: Discussionsupporting

confidence: 51%

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Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

et al. 2019

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Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET‐activating mutated variants that are either sensitive or resistant toward MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib‐sensitive cells. Moreover, prior to the induction of MET inhibition‐dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism, and of numerous TCA cycle‐related metabolites such as succinate, malate, and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential, and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor‐sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti‐MET therapies.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 51%

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

et al. 2019

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“…Changes in the PPP activity can affect response to anticancer drugs, however the specific role of PPP in MDR phenotype is still unclear. Other authors implied that PPP is more active in MDR tumors2728. Moreover, evidence suggested that elevated levels of NADPH and GSH, together with an active PPP, play an important role in MDR2930.…”

Section: Discussionmentioning

confidence: 99%

Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles

Lopes-Rodrigues

Luca

Mleczko

et al. 2017

Sci Rep

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Multidrug resistance (MDR) is a serious obstacle to efficient cancer treatment. Overexpression of P-glycoprotein (P-gp) plays a significant role in MDR. Recent studies proved that targeting cellular metabolism could sensitize MDR cells. In addition, metabolic alterations could affect the extracellular vesicles (EVs) cargo and release. This study aimed to: i) identify metabolic alterations in P-gp overexpressing cells that could be involved in the development of MDR and, ii) identify a potential role for the EVs in the acquisition of the MDR. Two different pairs of MDR and their drug-sensitive counterpart cancer cell lines were used. Our results showed that MDR (P-gp overexpressing) cells have a different metabolic profile from their drug-sensitive counterparts, demonstrating decreases in the pentose phosphate pathway and oxidative phosphorylation rate; increases in glutathione metabolism and glycolysis; and alterations in the methionine/S-adenosylmethionine pathway. Remarkably, EVs from MDR cells were capable of stimulating a metabolic switch in the drug-sensitive cancer cells, towards a MDR phenotype. In conclusion, obtained results contribute to the growing knowledge about metabolic alterations in MDR cells and the role of EVs in the intercellular transfer of MDR. The specific metabolic alterations identified in this study may be further developed as targets for overcoming MDR.

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“…In the nonoxidative phase, the pentose phosphates produced during the oxidative phase are recycled into glucose 6-phosphate. By providing cells with ribonucleotides for nucleic acid synthesis, and NADPH for lipid synthesis and redox homeostasis, PPP plays a critical role in cancer cell metabolism and often become activated in various cancers including solid tumors [8], AML [22], multiple myeloma [23], and lymphoid leukemias [24]. Inhibition of PPP in cancer cell lines reduces NADPH levels, lipid synthesis, and also reprograms metabolism by increasing oxidative phosphorylation [22] or glycolysis.…”

Section: Increased Glucose Metabolism Supports Anabolism and Redoxmentioning

confidence: 99%

Cell intrinsic and extrinsic regulation of leukemia cell metabolism

Jiang

Nakada

2016

Int J Hematol

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consumption through glycolysis even in the presence of oxygen (aerobic glycolysis) was initially hypothesized to be due to defective mitochondria [2]. However, more recent studies have established that many cancer cells harbor and are dependent upon functional mitochondria [3][4][5][6]. The question why cancer cells preferentially use glycolysis, an uneconomical route to produce ATP compared to mitochondrial oxidative phosphorylation, is beginning to be addressed in cancer cells. Glycolysis is not the dominant mechanism for many cancer cells to produce ATP, and ATP production is not the limiting factor for proliferation [7]. Rather, glycolysis offers cancer cells with metabolites essential for rapid division through metabolic pathways that branch away from glycolysis. For example, glucose-6-phosphate can be diverted to the pentose phosphate pathway (PPP) to produce reducing agents NADPH and ribonucleotides [8]. Additionally, 3-phospho-glycerate can enter the one-carbon cycle to generate amino acids, lipids, and reducing agents [9]. Thus, increased glycolysis meets the demand of proliferative cancer cells for anabolism, producing metabolic intermediates through multiple branching pathways. The decision of how cancer cells divert glycolysis intermediates remains elusive, but it is likely to be affected by cellular metabolic state and the environment in which the cancer cells are exposed.The metabolic milieu of the tumor microenvironment dictates the behavior of tumors. Tumors are exposed to nutrient-and oxygen-poor conditions as they grow exponentially due to insufficient vascularization [10]. Metabolic adaptation to these stress conditions is vital for tumor survival and expansion, and as such multiple metabolic regulators that enable metabolic adaptation are dysregulated in cancer. These include the components of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling that feeds into the mechanistic target of rapamycin (mTOR) pathway, Abstract Metabolic homeostasis is a fundamental property of cells that becomes dysregulated in cancer to meet the altered, often heightened, demand for metabolism for increased growth and proliferation. Oncogenic mutations can directly change cellular metabolism in a cell-intrinsic manner, priming cells for malignancy. Additionally, cellextrinsic cues from the microenvironment, such as hypoxia, nutrient availability, oxidative stress, and crosstalk from surrounding cells can also affect cancer cell metabolism, and produce metabolic heterogeneity within the tumor. Here, we highlight recent findings revealing the complexity and adaptability of leukemia cells to coordinate metabolism.

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Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway

Cited by 28 publications

References 33 publications

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles

Cell intrinsic and extrinsic regulation of leukemia cell metabolism

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