{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T20:58:14Z","timestamp":1785877094301,"version":"3.56.0"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,3,21]],"date-time":"2013-03-21T00:00:00Z","timestamp":1363824000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2013,5]]},"abstract":"Abstract<\/jats:title>TSC1<\/jats:styled-content><\/jats:italic> is often mutated in bladder cancer. However the importance of this event in disease pathogenesis and its implications for therapy are uncertain. We used genomic sequencing to examine the involvement of TSC1<\/jats:styled-content><\/jats:italic> in bladder cancer, and signalling pathway analysis and small\u2010molecule screening to identify targeted therapeutic strategies in TSC1<\/jats:styled-content><\/jats:italic> mutant bladder cancer cell lines. TSC1<\/jats:styled-content><\/jats:italic> loss of heterozygosity was seen in 54% of bladder cancers. Two (4.9%) of these 41 bladder cancers had TSC1<\/jats:styled-content><\/jats:italic> mutations by exon\u2010based sequencing. Analysis of 27 bladder cancer cell lines demonstrated inactivating TSC1<\/jats:styled-content><\/jats:italic> mutations in three: RT<\/jats:styled-content>\u20104, HCV29<\/jats:styled-content>, 97\u20131. Interestingly, only RT<\/jats:styled-content>\u20104 showed classic feedback inhibition of AKT<\/jats:styled-content>, and was highly sensitive to treatment with mTOR<\/jats:styled-content> inhibitors rapamycin and Torin1. 97\u20131 cells showed constitutive EGFR<\/jats:styled-content> activation, and were highly sensitive to combined treatment with the mTOR<\/jats:styled-content> inhibitor Torin1 and EGFR<\/jats:styled-content> inhibitors Lapatinib or Afatinib. A BRAF<\/jats:styled-content><\/jats:italic> missense mutation G469V<\/jats:styled-content> was found in HCV29<\/jats:styled-content> cells, and AKT<\/jats:styled-content> activation was dependent on BRAF<\/jats:styled-content>, but independent of ERK<\/jats:styled-content>. A kinase inhibitor screen of HCV29<\/jats:styled-content> cells showed strong growth inhibition by the Hsp90 inhibitor NVP\u2010AUY922<\/jats:styled-content>, and we then found synergistic inhibitory effects of NVP\u2010AUY922<\/jats:styled-content> combined with either Torin1 or rapamycin on cell survival for both HCV29<\/jats:styled-content> and 97\u20131 cells. In aggregate, these findings indicate that there are highly variable mutation profiles and signalling pathway activation in TSC1<\/jats:styled-content>\u2010mutant bladder cancer. Furthermore, combined Hsp90\/mTOR<\/jats:styled-content> inhibition is a promising therapeutic approach for TSC1<\/jats:styled-content><\/jats:italic> mutant bladder cancer. Copyright \u00a9 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:bold><\/jats:p>","DOI":"10.1002\/path.4176","type":"journal-article","created":{"date-parts":[[2013,2,7]],"date-time":"2013-02-07T16:02:06Z","timestamp":1360252926000},"page":"17-27","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["TSC1<\/scp><\/i> involvement in bladder cancer: diverse effects and\u00a0therapeutic implications"],"prefix":"10.1002","volume":"230","author":[{"given":"Yanan","family":"Guo","sequence":"first","affiliation":[{"name":"Division of Translational Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Chekaluk","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Du","sequence":"additional","affiliation":[{"name":"Broad Institute of Harvard University and Massachusetts Institute of Technology Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathanael S","family":"Gray","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin\u2010Lee","family":"Wu","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Urology Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J","family":"Kwiatkowski","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,3,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.20138"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-199812000-00001"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2008.07961.x"},{"key":"e_1_2_7_5_1","first-page":"1671","article-title":"Detailed deletion mapping of chromosome 9q in bladder cancer: evidence for two tumour suppressor loci","volume":"11","author":"Habuchi T","year":"1995","journal-title":"Oncogene"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ju.0000067626.37837.3e"},{"key":"e_1_2_7_7_1","first-page":"7652","article-title":"Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder","volume":"63","author":"Knowles MA","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-009-9198-3"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn098"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urolonc.2010.04.003"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1226344"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527630073"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202476899"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-4158"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3025"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1199498"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1199484"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5327.805"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500451200"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317222"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200403069"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M900301200"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106148"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1513"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205794"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604108"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007887"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2005.03.015"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000236"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07423"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.20957"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0646"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09454"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018583"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28984"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.08.014"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.12.023"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0778-09.2009"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8794-2-8"},{"key":"e_1_2_7_40_1","article-title":"Identification of nine genomic regions of amplification in urothelial carcinoma, correlation with stage, and potential prognostic and therapeutic value","author":"Yvonne C","year":"2013","journal-title":"PLOS ONE"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4176","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4176","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T10:42:49Z","timestamp":1760956969000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.4176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3,21]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,5]]}},"alternative-id":["10.1002\/path.4176"],"URL":"https:\/\/doi.org\/10.1002\/path.4176","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,3,21]]},"assertion":[{"value":"2012-12-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-02-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-03-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}