{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:04:07Z","timestamp":1753869847505,"version":"3.41.2"},"reference-count":19,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2017,4,14]],"date-time":"2017-04-14T00:00:00Z","timestamp":1492128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008258","name":"Hyundai Hope On Wheels","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008258","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Medulloblastoma is the most common malignant brain tumor of childhood. To identify targetable vulnerabilities, we employed inhibitor screening that revealed mTOR inhibitor hypersensitivity in the MYC\u2010overexpressing medulloblastoma cell line, D341. Concomitant exome sequencing unveiled an uncharacterized missense mutation, TSC2<jats:sup>A415V<\/jats:sup>, in these cells. We biochemically demonstrate that the TSC2<jats:sup>A415V<\/jats:sup> mutation is functionally deleterious, leading to shortened half\u2010life and proteasome\u2010mediated protein degradation. These data suggest that MYC cooperates with activated kinase pathways, enabling pharmacologic intervention in these treatment refractory tumors. We propose that identification of activated kinase pathways may allow for tailoring targeted therapy to improve survival and treatment\u2010related morbidity in medulloblastoma.<\/jats:p>","DOI":"10.1002\/pbc.26553","type":"journal-article","created":{"date-parts":[[2017,4,14]],"date-time":"2017-04-14T09:02:45Z","timestamp":1492160565000},"source":"Crossref","is-referenced-by-count":2,"title":["Functional validation of the oncogenic cooperativity and targeting potential of tuberous sclerosis mutation in medulloblastoma using a MYC\u2010amplified model cell line"],"prefix":"10.1002","volume":"64","author":[{"given":"Jacob J.","family":"Henderson","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Doernbecher Children's Hospital Pap\u00e9 Pediatric Research Institute, Oregon Health and Science University  Portland Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob P.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute Oregon Health and Science University  Portland Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolle E.","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Doernbecher Children's Hospital Pap\u00e9 Pediatric Research Institute, Oregon Health and Science University  Portland Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher A.","family":"Eide","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute Oregon Health and Science University  Portland Oregon"},{"name":"Howard Hughes Medical Institute  Portland Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoon\u2010Jae","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Doernbecher Children's Hospital Pap\u00e9 Pediatric Research Institute, Oregon Health and Science University  Portland Oregon"},{"name":"Department of Pediatric Neurology Doernbecher Children's Hospital, Oregon Health and Science University  Portland Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian J.","family":"Druker","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute Oregon Health and Science University  Portland Oregon"},{"name":"Howard Hughes Medical Institute  Portland Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika A.","family":"Davare","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Doernbecher Children's Hospital Pap\u00e9 Pediatric Research Institute, Oregon Health and Science University  Portland Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,4,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/not151"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.28.5148"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11284"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0b013e32834ec106"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198056"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12253-014-9771-0"},{"issue":"4","key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s004010100393","article-title":"Analysis of the TSC2 gene in human medulloblastoma","volume":"102","author":"Przkora R","year":"2001","journal-title":"Acta Neuropathol (Berl)"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1299"},{"issue":"23","key":"e_1_2_8_10_1","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1182\/blood.V126.23.3765.3765","article-title":"Phase Ib trial of the mTOR inhibitor Everolimus given in combination with multiagent chemotherapy in relapsed acute lymphoblastic leukemia","volume":"126","author":"Place AE","year":"2015","journal-title":"Blood"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24523"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-198901000-00005"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1515281112"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1319583110"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2016.01.025"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11003"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204009"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1086\/302381"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.25851"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.02.011"}],"container-title":["Pediatric Blood &amp; 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