{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T20:07:26Z","timestamp":1758398846501,"version":"3.41.2"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T00:00:00Z","timestamp":1646870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K00CA245821, R21CA263133"],"award-info":[{"award-number":["K00CA245821, R21CA263133"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001771","name":"Tuberous Sclerosis Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001771","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001502","name":"Blue Cross Blue Shield of Michigan Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001502","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>The tuberous sclerosis complex (TSC) is a rare genetic syndrome and multisystem disease resulting in tumor formation in major organs. A molecular hallmark of TSC is a dysregulation of the mammalian target of rapamycin (mTOR) through loss-of-function mutations in either tumor suppressor <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic>. Here, we sought to identify drug vulnerabilities conferred by TSC2 tumor-suppressor loss through cell-based chemical biology screening. Our small-molecule chemical screens reveal a sensitivity to inhibitors of checkpoint kinase 1\/2 (CHK1\/2), regulators of cell cycle, and DNA damage response, in both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> models of TSC2-deficient renal angiomyolipoma (RA) tumors. Further, we performed transcriptional profiling on TSC2-deficient RA cell models and discovered that these recapitulate some of the features from TSC patient kidney tumors compared to normal kidneys. Taken together, our study provides a connection between mTOR-dependent tumor growth and CHK1\/2, highlighting the importance of CHK1\/2 inhibition as a potential antitumor strategy in TSC2-deficient tumors.<\/jats:p>","DOI":"10.3389\/fonc.2022.852859","type":"journal-article","created":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T11:59:17Z","timestamp":1646913557000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Chemical Biology Screening Identifies a Vulnerability to Checkpoint Kinase Inhibitors in TSC2-Deficient Renal Angiomyolipomas"],"prefix":"10.3389","volume":"12","author":[{"given":"Robert M.","family":"Vaughan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer J.","family":"Kordich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Yuan","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanda K.","family":"Sasi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie L.","family":"Celano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kellie A.","family":"Sisson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Van Baren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew G.","family":"Kortus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dean J.","family":"Aguiar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey P.","family":"MacKeigan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1086\/316951","article-title":"Mutational Analysis in a Cohort of 224 Tuberous Sclerosis Patients Indicates Increased Severity of TSC2, Compared With TSC1, Disease in Multiple Organs","volume":"68","author":"Dabora","year":"2001","journal-title":"Am J Hum Genet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005637","article-title":"Mosaic and Intronic Mutations in TSC1\/TSC2 Explain the Majority of TSC Patients With No Mutation Identified by Conventional Testing","volume":"11","author":"Tyburczy","year":"2015","journal-title":"PloS Genet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15816","article-title":"The Genomic Landscape of Tuberous Sclerosis Complex","volume":"8","author":"Martin","year":"2017","journal-title":"Nat Commun"},{"key":"B4","unstructured":"Mendelian Inheritance in Man and its Online Version, OMIM\n            McKusickVA\n          2007"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323","article-title":"The Tuberous Sclerosis Complex","volume":"355","author":"Crino","year":"2006","journal-title":"N\u00a0Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nov152","article-title":"Differentiating the mTOR Inhibitors Everolimus and Sirolimus in the Treatment of Tuberous Sclerosis Complex","volume":"17","author":"MacKeigan","year":"2015","journal-title":"Neuro Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-016-3474-6","article-title":"Treatment of Renal Angiomyolipoma in Tuberous Sclerosis Complex (TSC) Patients","volume":"32","author":"Brakemeier","year":"2017","journal-title":"Pediatr Nephrol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2015.05.016","article-title":"Long-Term Follow-Up Assessing Renal Angiomyolipoma Treatment Patterns, Morbidity, and Mortality: An Observational Study in Tuberous Sclerosis Complex Patients in the Netherlands","volume":"66","author":"Eijkemans","year":"2015","journal-title":"Am J Kidney Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ncb839","article-title":"TSC2 Is Phosphorylated and Inhibited by Akt and Suppresses mTOR Signalling","volume":"4","author":"Inoki","year":"2002","journal-title":"Nat Cell Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa063564","article-title":"Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis","volume":"358","author":"Bissler","year":"2008","journal-title":"N Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1100391","article-title":"Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis","volume":"364","author":"McCormack","year":"2011","journal-title":"N Engl J Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1001671","article-title":"Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis","volume":"363","author":"Krueger","year":"2010","journal-title":"N Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61134-9","article-title":"Efficacy and Safety of Everolimus for Subependymal Giant Cell Astrocytomas Associated With Tuberous Sclerosis Complex (EXIST-1): A Multicentre, Randomised, Placebo-Controlled Phase 3 Trial","volume":"381","author":"Franz","year":"2013","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182815428","article-title":"Everolimus Long-Term Safety and Efficacy in Subependymal Giant Cell Astrocytoma","volume":"80","author":"Krueger","year":"2013","journal-title":"Neurology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"3015","DOI":"10.1038\/s41598-019-39418-5","article-title":"Rapalog Resistance Is Associated With Mesenchymal-Type Changes in Tsc2-Null Cells","volume":"9","author":"Valianou","year":"2019","journal-title":"Sci Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.04.027","article-title":"mTOR-Raptor Binds and Activates SGK1 to Regulate P27 Phosphorylation","volume":"30","author":"Hong","year":"2008","journal-title":"Mol Cell"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00204.2003","article-title":"Estradiol and Tamoxifen Stimulate LAM-Associated Angiomyolipoma Cell Growth and Activate Both Genomic and Nongenomic Signaling Pathways","volume":"286","author":"Yu","year":"2004","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2119\/2006-00070.Lim","article-title":"Expression of the Neural Stem Cell Markers NG2 and L1 in Human Angiomyolipoma: Are Angiomyolipomas Neoplasms of Stem Cells","volume":"13","author":"Lim","year":"2007","journal-title":"Mol Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1158\/1541-7786.MCR-13-0258-T","article-title":"Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide","volume":"12","author":"Parkhitko","year":"2014","journal-title":"Mol Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-8-14","article-title":"Comparison of Three Rapamycin Dosing Schedules in A\/J Tsc2+\/- Mice and Improved Survival With Angiogenesis Inhibitor or Asparaginase Treatment in Mice with Subcutaneous Tuberous Sclerosis Related Tumors","volume":"8","author":"Woodrum","year":"2010","journal-title":"J Transl Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.141","article-title":"Simultaneous Isolation of High-Quality DNA, RNA, miRNA and Proteins From Tissues for Genomic Applications","volume":"8","author":"Pe\u00f1a-Llopis","year":"2013","journal-title":"Nat Protoc"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0492","article-title":"AZD7762, A Novel Checkpoint Kinase Inhibitor, Drives Checkpoint Abrogation and Potentiates DNA-Targeted Therapies","volume":"7","author":"Zabludoff","year":"2008","journal-title":"Mol Cancer Ther"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-013-0036-7","article-title":"Characterization and Preclinical Development of LY2603618: A Selective and Potent Chk1 Inhibitor","volume":"32","author":"King","year":"2014","journal-title":"Invest New Drugs"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10662","article-title":"Lysosomal Recruitment of TSC2 is a Universal Response to Cellular Stress","volume":"7","author":"Demetriades","year":"2016","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17222","article-title":"Loss of Tsc1\/Tsc2 Activates mTOR and Disrupts PI3K-Akt Signaling Through Downregulation of PDGFR","volume":"112","author":"Zhang","year":"2003","journal-title":"J Clin Invest"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust Enumeration of Cell Subsets From Tissue Expression Profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e98674","DOI":"10.1172\/jci.insight.98674","article-title":"TSC2-Deficient Tumors Have Evidence of T Cell Exhaustion and Respond to Anti\u2013PD-1\/Anti\u2013CTLA-4 Immunotherapy","volume":"3","author":"Liu","year":"2018","journal-title":"JCI Insight"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2380-5","article-title":"Phase I Dose-Escalation Study of AZD7762, A Checkpoint Kinase Inhibitor, in Combination With Gemcitabine in US Patients With Advanced Solid Tumors","volume":"73","author":"Sausville","year":"2014","journal-title":"Cancer Chemother Pharmacol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00577-16","article-title":"mTORC1 and -2 Coordinate Transcriptional and Translational Reprogramming in Resistance to DNA Damage and Replicative Stress in Breast Cancer Cells","volume":"37","author":"Silvera","year":"2017","journal-title":"Mol Cell Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-017-0033-8","article-title":"The mTOR-S6K Pathway Links Growth Signalling to DNA Damage Response by Targeting RNF168","volume":"20","author":"Xie","year":"2018","journal-title":"Nat Cell Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2018.06.011","article-title":"mTORC1 Pathway in DNA Damage Response","volume":"1865","author":"Ma","year":"2018","journal-title":"Biochim Biophys Acta Mol Cell Res"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.852859\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T11:59:22Z","timestamp":1646913562000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.852859\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,10]]},"references-count":31,"alternative-id":["10.3389\/fonc.2022.852859"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.852859","relation":{},"ISSN":["2234-943X"],"issn-type":[{"type":"electronic","value":"2234-943X"}],"subject":[],"published":{"date-parts":[[2022,3,10]]},"article-number":"852859"}}