Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma

Qie, Shuo; Yoshida, Akihiro; Parnham, Stuart; Oleinik, Natalia; Beeson, Gyda; Beeson, Craig C.; Öğretmen, Besim; Bass, Adam J.; Wong, Kwok‐Kin; Rustgi, Anil K.; Diehl, J. Alan

doi:10.1038/s41467-019-09179-w

Cited by 80 publications

(65 citation statements)

References 64 publications

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“…A combinatorial strategy may help to overcome glutaminase inhibition resistance. Several inhibitors targeting glycolysis have demonstrated a synergistic effect with glutaminase inhibitor, such as metformin (115,143,144), Erlotinib (EGFR inhibitor) (145), MLN128 (mTOR inhibitor) (52), and Glutor (glucose uptake inhibitor) (146). Co-inhibition of FAO with etomoxir (CPT1 inhibitor) as well inhibits the cell proliferation in resistant cells (130,142).…”

Section: Glutaminase Inhibitor Based Therapeutic Strategymentioning

confidence: 99%

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

et al. 2020

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Metabolism rewiring is an important hallmark of cancers. Being one of the most abundant free amino acids in the human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, and the production of antioxidants through glutaminolysis in cancers. In glutamine dependent cancer cells, more than half of the tricarboxylic/critic acid (TCA) metabolites are derived from glutamine. Glutaminolysis controls the process of converting glutamine into TCA cycle metabolites through the regulation of multiple enzymes, among which the glutaminase shows the importance as the very first step in this process. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Here, we review the regulation of glutaminase and the role of glutaminase in cancer metabolism and metastasis. Furthermore, we highlight the glutaminase inhibitor based metabolic therapy strategy and their potential applications in clinical scenarios.

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Section: Glutaminase Inhibitor Based Therapeutic Strategymentioning

confidence: 99%

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

et al. 2020

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“…This differential regulation of mTORC1 and mTORC2 is mediated by sestrin2 and Glutamine is a versatile molecule, as it serves as an alternative carbon source for energy production and its carbon and nitrogen are also used for biosynthetic reactions [130]. Hence, cancer cells can develop addiction to glutamine and upregulate its metabolism to provide necessary building blocks for the growing tumor [131,132]. mTOR has been linked to the regulation of many of these processes.…”

Section: Glutamine Metabolismmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…For example, Obrist et al conducted mass spectrometric metabolomics and specific interventions on glutamine metabolism and found that glutamine was majorly utilized for nucleotide biosynthesis rather than for bioenergetic, anaplerotic or redox reactions in cisplatin-resistant NSCLC and ovarian cancer cells [74]. The reprogramming of glutaminolysis via the Fbxo4-cyclin D1 axis was reported to contribute to CDK4/6 inhibitor resistance in human ESCC [75]. Disruption of glutamine metabolic pathways could enhance the drug responsiveness of pancreatic cancer to gemcitabine treatment [76].…”

Section: Amino Acid Metabolismmentioning

confidence: 99%

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Guo

Tan

Chen

et al. 2020

Cancers

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Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

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Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma

Cited by 80 publications

References 64 publications

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

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