{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:55:10Z","timestamp":1790794510003,"version":"4.1.0"},"reference-count":77,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":51,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CDMRP NFRP","award":["W81XWH2210324"],"award-info":[{"award-number":["W81XWH2210324"]}]},{"name":"St. Louis Men\u2019s Group Against Cancer","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"The Neurofibromatosis Therapeutic Acceleration Program","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/01359dk79","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NINDS","award":["1R01NS134815-01"],"award-info":[{"award-number":["1R01NS134815-01"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NCI Cancer Center","award":["#P30 CA091842"],"award-info":[{"award-number":["#P30 CA091842"]}]},{"name":"Battelle Memorial Institute","award":["DE-AC05-76RL01830"],"award-info":[{"award-number":["DE-AC05-76RL01830"]}],"id":[{"id":"https:\/\/ror.org\/01h5tnr73","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>\n                    Aneuploidy is a hallmark of cancer often associated with inferior prognosis. Copy number gains of chromosome 8 (chr8) are recurrent in multiple cancers, including breast, prostate, and colorectal cancers, and sarcomas, such as malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive, hard-to-treat sarcomas frequently linked to the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. To investigate the role of chr8 gain in MPNST pathogenesis, we performed a CRISPR-knockout screen and identified 58 essential genes on chr8, including\n                    <jats:italic>PTK2<\/jats:italic>\n                    , which encodes focal adhesion kinase (FAK). We evaluated FAK as a therapeutic target and tested small-molecule FAK inhibitors (FAKi) alone or combined with RAF\/MEK inhibitors (RAF\/MEKi), a class of agents relevant to NF1-deficient tumors with ERK pathway hyperactivation. Both pharmacological and genetic inhibition of FAK reduced MPNST cell proliferation in vitro and tumor growth in vivo. Combined FAKi and RAF\/MEKi treatment further suppressed phosphorylation of FAK, STAT3, and AKT while increasing cleaved caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1), indicating enhanced apoptosis. In MPNST patient-derived xenograft (PDX) models, combination therapy significantly reduced tumor growth, showing superior efficacy, particularly in chr8 gain MPNST PDX. These results support FAK\/RAF\/MEK cotargeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.\n                  <\/jats:p>","DOI":"10.1172\/jci201331","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:00:38Z","timestamp":1786464038000},"source":"Crossref","is-referenced-by-count":0,"title":["Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors"],"prefix":"10.1172","volume":"136","author":[{"given":"Guangfeng","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana C.","family":"Borcherding","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuzhan","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gorkem","family":"Oztosun","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Sears","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangwen","family":"Xiao","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda B.","family":"Garana","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark I.","family":"Zoberi","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron U.","family":"Bektas","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey J.","family":"Szymanski","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richa","family":"Rathore","sequence":"additional","affiliation":[{"name":"Verastem Oncology, Needham, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Coma","sequence":"additional","affiliation":[{"name":"Verastem Oncology, Needham, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Pachter","sequence":"additional","affiliation":[{"name":"Verastem Oncology, Needham, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara J.C.","family":"Gosline","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, Washington, USA."},{"name":"Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, Oregon, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7116-0605","authenticated-orcid":true,"given":"Christine A.","family":"Pratilas","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-0771","authenticated-orcid":true,"given":"Angela C.","family":"Hirbe","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in St. Louis School of Medicine and Siteman Cancer Center, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1382021"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-024-01078-5"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdz047"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/children9010038"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx124"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-015-0328-6"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/8685638"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-3760"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.omto.2023.07.008"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/cells9112365"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4693-04.2005"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.1068452"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.903177"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60578"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.28639"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0189"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-1365"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-1992"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3095"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15183-1"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-0786"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noad097"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.146351"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.apjo.2024.100108"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1101\/gad.345454.120"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.18.1574"},{"issue":"6","key":"B27","first-page":"1201","article-title":"Glutathione reductase (GSR) gene deletion and chromosome 8 aneuploidy in primary lung cancers detected by fluorescence in situ hybridization","volume":"9","author":"Baity","year":"2019","journal-title":"Am J Cancer Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3937"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.03.011"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07922-3"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.191321998"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031726"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.79.0543"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1200\/JCO-25-00112"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.910505"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-023-02582-4"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-020-01298-3"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-016-0157-7"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47423-0"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-025-03461-6"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2019.10.033"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-015-0282-y"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-024-02727-2"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.47327"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2785"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61350"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.008"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2012.01.065"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1136\/ijgc-2024-005919"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/mc.20552"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26051973"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101780"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.268"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17020161"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3390\/cells8020147"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.10.082"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.102976"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.2174\/0118715206346843241119105519"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.28505"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00135"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2316733121"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.21037\/jgo-20-574"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.9b00918"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.7150\/jca.60885"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.4103\/jcrt.jcrt_1072_22"},{"issue":"4","key":"B66","first-page":"372","article-title":"[Methylated SDC2 testing in stool DNA for early screening of colorectal cancer in Shipai Town, Dongguan City]","volume":"26","author":"Kong","year":"2023","journal-title":"Zhonghua Wei Chang Wai Ke Za Zhi"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19900915)66:6<1253::AID-CNCR2820660627>3.0.CO;2-R"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-827"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-3049"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-020-0508-5"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-025-05433-7"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-1172"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710052104"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004873"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0439-x"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/201331\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:01:26Z","timestamp":1790791286000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/201331"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":77,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,8,11]]},"published-print":{"date-parts":[[2026,10,1]]}},"alternative-id":["10.1172\/JCI201331"],"URL":"https:\/\/doi.org\/10.1172\/jci201331","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"article-number":"e201331"}}