气候变化领域集成服务门户(CCPortal): Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma

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DOI	10.1073/PNAS.2009620118
	Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma
	Dalton K.M.; Lochmann T.L.; Floros K.V.; Calbert M.L.; Kurupi R.; Stein G.T.; McClanaghan J.; Murchie E.; Egan R.K.; Greninger P.; Dozmorov M.; Ramamoorthy S.; Puchalapalli M.; Hu B.; Shock L.; Koblinski J.; Glod J.; Boikos S.A.; Benes C.H.; Faber A.C.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	MYCN-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an "Achilles' heel" and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that MYCN-amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in MYCNamplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of MYCNamplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-bloodcell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for MYCN-amplified neuroblastoma that demonstrates efficacy and tolerability in vivo. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Apoptosis; Lactate; Metabolomics; MYCN; Neuroblastoma
语种	英语
scopus关键词	adenosine triphosphate; CD147 antigen; monocarboxylate transporter 1; monocarboxylate transporter 2; phenformin; animal experiment; animal model; animal tissue; Article; cell death; controlled study; correlational study; endoplasmic reticulum stress; gene; gene amplification; gene expression; glycolysis; human; human cell; mouse; MYCN gene; neuroblastoma; nonhuman; oxidative phosphorylation; priority journal
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180053
作者单位	Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States; Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA 02129, United States; Department of Medicine, Harvard Medical School, Boston, MA 02115, United States; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, United States; Discovery and Translational Sciences Metabolon Inc., Research Triangle Park, NC 27709, United States; Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, United States; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, United States; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States
推荐引用方式 GB/T 7714	Dalton K.M.,Lochmann T.L.,Floros K.V.,et al. Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma[J],2021,118(13).
APA	Dalton K.M..,Lochmann T.L..,Floros K.V..,Calbert M.L..,Kurupi R..,...&Faber A.C..(2021).Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Dalton K.M.,et al."Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).