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In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre\/HrasG12V\/p53flox\/flox) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS\u2013MAPK signaling was abrogated in vitro by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective in vivo, whereas combination of tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor-bearing mice treated with tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a Nf1 nonsense mutation and an activating mutation in Gnas at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance in vivo. This study demonstrates the feasibility of targeting Ras membrane association in cancers in vivo and predicts combination therapies that confer additional benefit.<\/jats:p>\n               <jats:p>Significance: Tipifarnib effectively inhibits oncogenic HRAS-driven tumorigenesis and abrogating adaptive signaling improves responses. NF1 and GNAS mutations drive acquired resistance to Hras inhibition, supporting the on-target effects of the drug. Cancer Res; 78(16); 4642\u201357. \u00a92018 AACR.<\/jats:p>","DOI":"10.1158\/0008-5472.can-17-1925","type":"journal-article","created":{"date-parts":[[2018,5,14]],"date-time":"2018-05-14T14:40:17Z","timestamp":1526308817000},"page":"4642-4657","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers"],"prefix":"10.1158","volume":"78","author":[{"given":"Brian R.","family":"Untch","sequence":"first","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"2Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Dos Anjos","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.R.","family":"Garcia-Rendueles","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Knauf","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gnana P.","family":"Krishnamoorthy","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Saqcena","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umeshkumar K.","family":"Bhanot","sequence":"additional","affiliation":[{"name":"3Pathology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D.","family":"Socci","sequence":"additional","affiliation":[{"name":"4Marie-Jos\u00e9e & Henry R. 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