Targeted inhibition of glutaminase as a potential new approach for the treatment of NF1 associated soft tissue malignancies
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Tahir N. Sheikh1,*, Parag P. Patwardhan1,*, Serge Cremers2 and Gary K. Schwartz1,3
1Herbert Irving Comprehensive Cancer Center, New York, NY, USA
2Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
3Department of Hematology/Oncology, Columbia University College of Medicine, New York, NY, USA
*These authors have contributed equally to this work
Parag P. Patwardhan, email: email@example.com
Keywords: NF1, glutaminase, CB-839, glutamine, soft-tissue sarcoma
Received: June 08, 2017 Accepted: September 16, 2017 Published: October 06, 2017
Many cancer cells rely on glutamine as the source of carbon molecules to feed the biosynthetic pathways and are often addicted to glutaminolysis. Inhibitors of glutaminase activity have gained attention in the last few years due to their anti-proliferative effect and ability to induce apoptosis in some cancers. Although it is a promising therapeutic approach, its efficacy or the role played by glutamine in modulating cell proliferation in NF1 associated tumors has never been studied. We report for the first time, a strong correlation between the NF1 status of tumor cells and increased sensitivity to glutamine deprivation and glutaminase inhibition. Soft-tissue cell lines null for NF1 were highly dependent on glutamine for proliferation and showed decreased mTORC1 and Ras activity in response to glutaminase inhibition. Re-addition of glutamine or intermediary metabolite such as glutamate to the media restored mTORC1 and Ras activity. SiRNA mediated NF1 knockdown in wild-type NF1 cell line shows increased sensitivity to glutaminase inhibition. Conversely, NF1 overexpression in NF1 null cell lines results in reduced sensitivity to glutaminase inhibition, and restores mTORC1 signaling and Ras activity. These findings provide new insights into the role played by glutamine metabolism in NF1 associated tumors and strongly warrant further investigation as a potential therapy in the NF1 disease setting.
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