{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T06:03:13Z","timestamp":1794204193124,"version":"4.8.0"},"reference-count":60,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"NIH NIDCR","doi-asserted-by":"crossref","award":["R01DE023641"],"award-info":[{"award-number":["R01DE023641"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH NCI","award":["R01CA234351"],"award-info":[{"award-number":["R01CA234351"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,8]]},"abstract":"<jats:p>\n                    No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a\n                    <jats:italic>CRTC1-MAML2<\/jats:italic>\n                    fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4\/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2\u2013induced tumorigenesis. Cotargeting of aberrant p16-CDK4\/6-RB signaling and CRTC1-MAML2 fusion\u2013activated AREG\/EGFR signaling with the respective CDK4\/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4\/6 inhibitors as a potential viable strategy for patients with MEC.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.139497","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T14:02:31Z","timestamp":1617804151000},"source":"Crossref","is-referenced-by-count":73,"title":["The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma"],"prefix":"10.1172","volume":"6","author":[{"given":"Zirong","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"UF Health Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5729-827X","authenticated-orcid":true,"given":"Wei","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"UF Health Cancer Center, and"},{"name":"Genetics & Genomics Graduate Program, UF Genetics Institute, University of Florida College of Medicine, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6487-081X","authenticated-orcid":true,"given":"Jian-Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuibin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"UF Health Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"UF Health Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer W.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, and"},{"name":"Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marino E.","family":"Leon","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria D.","family":"Hurtado","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Mayo Clinic Health System La Crosse, Wisconsin, USA, and"},{"name":"Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei","family":"Zolotukhin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, Yale New Haven Hospital, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4969-6040","authenticated-orcid":true,"given":"Jianrong","family":"Lu","sequence":"additional","affiliation":[{"name":"UF Health Cancer Center, and"},{"name":"Department of Biochemistry and Molecular Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic J.","family":"Kaye","sequence":"additional","affiliation":[{"name":"UF Health Cancer Center, and"},{"name":"Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0076-2617","authenticated-orcid":true,"given":"Lizi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"UF Health Cancer Center, and"},{"name":"Genetics & Genomics Graduate Program, UF Genetics Institute, University of Florida College of Medicine, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0135"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2091"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw282"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0113-0"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nm0596-561"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0168"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0757.2011.00385.x"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s12105-013-0432-5"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13952"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0791"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s004280050293"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/BF00311465"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e318190cf5b"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/his.13779"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2017.02.025"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e3181de3021"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2020.02.001"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2015.3270"},{"issue":"1","key":"B19","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1600-0714.2008.00676.x","article-title":"New insights into the nature of Warthin\u2019s tumour","volume":"38","author":"O\u2019Neill","year":"2009","journal-title":"J Oral Pathol Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2007.10.007"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3072"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20522"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/0165-4608(95)00266-9"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ng1083"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.228"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600719"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1125"},{"key":"B28","doi-asserted-by":"crossref","DOI":"10.1186\/s12885-015-1827-3","article-title":"Gene expression profiling analysis of CRTC1-MAML2 fusion oncogene-induced transcriptional program in human mucoepidermoid carcinoma cells","volume":"15","author":"Chen","year":"2015","journal-title":"BMC Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1319176111"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808749106"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209627"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.348"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-017-0104-0"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806213105"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1023\/A:1013063514007"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.1989.tb01572.x"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2013.05.013"},{"issue":"1","key":"B38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0146711","article-title":"Cell-specific cre strains for genetic manipulation in salivary glands","volume":"11","author":"Maruyama","year":"2016","journal-title":"PLoS One"},{"issue":"10","key":"B39","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0026137","article-title":"Salivary PYY: a putative bypass to satiety","volume":"6","author":"Acosta","year":"2011","journal-title":"PLoS One"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302691"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-0873-9"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20719"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-0894"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0143-7"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.26"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2419"},{"key":"B47","doi-asserted-by":"crossref","first-page":"454","DOI":"10.2741\/s164","article-title":"Advances in EGFR-directed therapy in head and neck cancer","volume":"3","author":"Numico","year":"2011","journal-title":"Front Biosci (Schol Ed)"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050753"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2013.08.004"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa216"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1097\/01.cad.0000127664.66472.60"},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms15916","article-title":"CDK4\/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers","volume":"8","author":"Vijayaraghavan","year":"2017","journal-title":"Nat Commun"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4554"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw689"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0720"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.06.005"},{"issue":"1","key":"B57","first-page":"24","article-title":"Immortalization of normal human salivary gland cells with duct-, myoepithelial-, acinar-, or squamous phenotype by transfection with SV40 ori- mutant deoxyribonucleic acid","volume":"69","author":"Azuma","year":"1993","journal-title":"Lab Invest"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1358-4"},{"issue":"49","key":"B59","doi-asserted-by":"crossref","DOI":"10.3791\/2573","article-title":"Clonogenic assay: adherent cells","author":"Rafehi","year":"2011","journal-title":"J Vis Exp"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/139497\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:44:34Z","timestamp":1779151474000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/139497"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,8]]},"references-count":60,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4,8]]},"published-print":{"date-parts":[[2021,4,8]]}},"alternative-id":["10.1172\/jci.insight.139497"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.139497","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,8]]},"article-number":"e139497"}}