Identifying strategies to target the metabolic flexibility of tumours

Méndez-Lucas, Andrés; Lin, Wei; Driscoll, Paul C.; Legrave, Nathalie; Novellasdemunt, Laura; Xie, Chencheng; Charles, Mark; Wilson, Zena; Jones, Neil P.; Rayport, Stephen; Rodriguez‐Justo, Manuel; Li, Vivian; MacRae, James I.; Hay, Nissim; Chen, Xin; Yuneva, Mariia

doi:10.1038/s42255-020-0195-8

Cited by 94 publications

(96 citation statements)

References 71 publications

(126 reference statements)

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“…GLS inhibition remarkably increases tumor free survival but upregulates compensatory mechanisms such as transamidases, HK2, FASN, and serine/glycine synthesis. Simultaneous inhibition of these pathways using combination therapy could synergistically suppress tumor growth [ 270 ].…”

Section: Therapeutic Interventions Targeting Cancer Metabolismmentioning

confidence: 99%

Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets

Park

Pyun

Park

2020

Cells

231

147

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Aberrant metabolism is a major hallmark of cancer. Abnormal cancer metabolism, such as aerobic glycolysis and increased anabolic pathways, has important roles in tumorigenesis, metastasis, drug resistance, and cancer stem cells. Well-known oncogenic signaling pathways, such as phosphoinositide 3-kinase (PI3K)/AKT, Myc, and Hippo pathway, mediate metabolic gene expression and increase metabolic enzyme activities. Vice versa, deregulated metabolic pathways contribute to defects in cellular signal transduction pathways, which in turn provide energy, building blocks, and redox potentials for unrestrained cancer cell proliferation. Studies and clinical trials are being performed that focus on the inhibition of metabolic enzymes by small molecules or dietary interventions (e.g., fasting, calorie restriction, and intermittent fasting). Similar to genetic heterogeneity, the metabolic phenotypes of cancers are highly heterogeneous. This heterogeneity results from diverse cues in the tumor microenvironment and genetic mutations. Hence, overcoming metabolic plasticity is an important goal of modern cancer therapeutics. This review highlights recent findings on the metabolic phenotypes of cancer and elucidates the interactions between signal transduction pathways and metabolic pathways. We also provide novel rationales for designing the next-generation cancer metabolism drugs.

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Section: Therapeutic Interventions Targeting Cancer Metabolismmentioning

confidence: 99%

Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets

Park

Pyun

Park

2020

Cells

231

147

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“…Previously, we showed that dysregulated Myc modulated the production of eicosanoids, critical for proliferation and cell survival, in lung adenocarcinoma (14). Other recent studies link Myc to increased lipogenesis in tumours (15,16), whilst switching from a high to low-fat diet attenuates the Myc transcriptional program in prostate cancer (17). It is evident that lipids and their interaction with oncogenes, such as Myc, play a complex and elegant role in tumorigenesis and offer an underexploited therapeutic avenue.…”

Section: Introductionmentioning

confidence: 81%

Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer

Hall

Wilson

Burkhart

et al. 2020

Journal of Lipid Research

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Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Whilst mutations in Kras and over-expression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc, in combination with surface analysis lipid profiling of lung tumours and transcriptomics, to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that activation of Myc leads to the accumulation of cholesteryl esters (CE), stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumours in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux and accumulation of CE-rich lipid droplets in lung tumours. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.

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“…function" cases where amplification of PHGDH leads to elevated rates of serine biosynthesis in basal tumors. However, it is becoming clear that targeting "gain-of-function" metabolic alterations in cancer can be challenging if redundant pathways remain present and active (Méndez-Lucas et al, 2020). Because our goal was to identify "loss-of-function" cases where pathway redundancy is limited by lineage-specific gene expression, we have identified a 15 potentially more tractable opportunity to target serine metabolism in luminal, not basal, breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…This and other work motivated the development of PHGDH inhibitors as potential 25 cancer treatments (Mullarky et al, 2016;Pacold et al, 2016;Rohde et al, 2018;Wang et al, 2017). While inhibition of serine synthesis has shown efficacy in some models and is still being evaluated, it is becoming clear that in some circumstances it is not effective due to extracellular serine that can be taken up to offset inhibition of de novo biosynthesis (Chen et al, 2013;Méndez-Lucas et al, 2020;Nilsson et al, 2012;Sullivan et al, 2019). Because our goal was to identify cases where lineage-dependent gene expression reduces pathway redundancy, we 5 examined whether the very low expression of PSAT1 found in luminal tumors limits their ability to synthesize serine and creates a dependency on exogenous serine for growth.…”

Section: Introductionmentioning

confidence: 99%