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Pancreatic Cancer Metabolism Published OnlineFirst March 3, 2017; DOI: 10.1158/2159-8290.CD-RW2017-044 RESEARCH WATCH Pancreatic Cancer Major finding: PanNET mutations affect Concept: Comprehensive molecular anal- Impact: The comprehensive identifica- DNA damage repair, chromatin remodeling, ysis of 102 clinically sporadic PanNETs tion of PanNET genetic alterations may telomere maintenance, and mTOR signaling. uncovers essential PanNET pathways. aid risk stratification and treatment. WHOLE-GENOME SEQUENCING DEFINES THE MUTATIONAL LANDSCAPE OF PanNETS Pancreatic neuroendocrine tumors (PanNET) are exhibited increased telomere length. There were classifi ed into three groups: low grade (G1), inter- an average of 29 structural rearrangements per mediate grade (G2), and high grade (G3). G3 Pan- tumor, with rearrangements leading to inactiva- NETs have a universally poor prognosis, whereas tion of tumor suppressors such as MTAP, ARID2, G1 and G2 tumors have an unpredictable clinical SMARCA4, MLL3, CDKN2A, and SETD2, or creating course. A better understanding of the molecular oncogenic gene fusions. In total, 66 somatic in- underpinnings of the disease may enable better frame gene fusions were identifi ed, including three risk stratifi cation and the identifi cation of patients EWSR1 fusion events leading to EWSR1–BEND2 or who might benefi t from early aggressive therapy. Scarpa and EWSR1–FLI1. Although EWSR1–FLI1 is a characteristic Ewing colleagues performed comprehensive molecular analyses of sarcoma fusion gene, the morphologic and pathologic features 102 clinically sporadic PanNETs. Whole-genome sequencing were consistent with PanNETs. RNA sequencing of 30 Pan- of 98 PanNETs defi ned fi ve distinct mutational signatures: NET tumors found that common genetic alterations affected MUTYH, APOBEC, BRCA-defi ciency, age, and COSMIC signa- DNA damage and repair, chromatin remodeling, telomere ture 5. The MUTYH signature was previously undescribed maintenance, and mTOR signaling, suggesting possible thera- and was associated with G:C>T:A transversions in tumors peutic targets. This comprehensive genomic analysis identifi ed with an inactivating germline mutation in the base excision– mutations, structural rearrangements, and signaling pathways repair gene MUTYH, suggesting that MUTYH defi ciency may not previously associated with PanNETs, which may aid in risk contribute to PanNET. Germline mutations were detected in stratifi cation and the development of targeted therapies. ■ MEN1, CDKN1B, CHEK2, and VHL1, in addition to BRCA1 and MUTYH. Further, 15,751 somatic coding mutations were Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, identifi ed in 2,787 genes, and MEN1 was the most frequently et al. Whole-genome landscape of pancreatic neuroendocrine tumours. mutated gene. Tumors with ATRX, DAXX, or MEN1 mutations Nature 2017;543:65–71. Metabolism Major finding: CKMT1 is highly expressed Mechanism: EVI1 binds the RUNX1 pro- Impact: Targeting CKMT1 to block the in EVI1-positive AML cells and promotes moter to reduce its expression, prevent- creatine kinase pathway may be benefi- their growth in vitro and in vivo. ing RUNX1-mediated CKMT1 repression. cial in patients with EVI1-driven AML. CKMT1 MAY BE A THERAPEUTIC TARGET IN EVI1-DRIVEN ACUTE MYELOID LEUKEMIA Chromosomal translocations promote aberrant RUNX1 by binding directly to its promoter, thereby alleviat- expression of the proto-oncogenic transcription factor EVI1 ing RUNX1-mediated repression of the CKMT1 promoter (also known as MECOM) to drive a subset of acute myeloid and enhancing CKMT1 expression. Moreover, primary AML leukemias (AML) that are associated with a poor clinical samples with high expression of CKMT1 were associated outcome. EVI1-driven AML is refractory to current therapies, with the subgroup of samples with high EVI1 expression and prompting Fenouille, Bassil, and colleagues to perform inte- low RUNX1 expression. Depletion or inhibition of CKMT1 grated genomic and metabolic screens to identify potential resulted in reduced metabolism of arginine to creatinine and druggable metabolic dependencies. Overexpression of EVI1 decreased intracellular ATP levels, indicating that CKMT1 is resulted in altered levels of many metabolites including required to promote mitochondrial activity. Cyclocreatine those involved in purine and pyrimidine metabolism, amino treatment reduced the viability of EVI1-expressing AML cells acid metabolism, the pentose phosphate pathway, and gly- by inhibiting the cell cycle and inducing apoptosis. In vivo, colysis. An shRNA screen of genes involved in these meta- pharmacologic or genetic inhibition of CKMT1 suppressed bolic pathways revealed that depletion of the ATP-buffering the progression of EVI1-positive AML and prolonged sur- mitochondrial creatine kinase CKMT1, an enzyme which vival, and reactivation of the creatine kinase pathway reversed promotes the metabolism of arginine to creatinine, sup- these effects. The identifi cation of the creatine kinase path- pressed the growth of EVI1-expressing AML cell lines, sug- way as a metabolic vulnerability in EVI1-positive leukemias gesting its potential as a therapeutic target. Further, analysis suggests that CKMT1 may be a potential therapeutic target of 68 primary AML samples showed that the samples with in these tumors. ■ the highest expression of EVI1 also exhibited high CKMT1 expression and enhanced sensitivity to cyclocreatine, a Fenouille N, Bassil CF, Ben-Sahra I, Benajiba L, Alexe G, Ramos small-molecule inhibitor of CKMT1. Mechanistically, EVI1 A, et al. The creatine kinase pathway is a metabolic vulnerability in reduced expression of the myeloid differentiation regulator EVI1-positive acute myeloid leukemia. Nat Med 2017;23:301–13. APRIL 2017CANCER DISCOVERY | 349 Downloaded from cancerdiscovery.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst March 3, 2017; DOI: 10.1158/2159-8290.CD-RW2017-044 Whole-Genome Sequencing Defines the Mutational Landscape of PanNETs Cancer Discov 2017;7:349. Published OnlineFirst March 3, 2017. Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2017-044 E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Subscriptions [email protected]. Permissions To request permission to re-use all or part of this article, use this link http://cancerdiscovery.aacrjournals.org/content/7/4/349.1. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site. Downloaded from cancerdiscovery.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. .
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