{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:01:44Z","timestamp":1790910104826,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019450","name":"Verastem Oncology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019450","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA\u201016359"],"award-info":[{"award-number":["CA\u201016359"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 CA176067\u201001A1"],"award-info":[{"award-number":["U01 CA176067\u201001A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>High\u2010grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS\/MAPK pathways, we evaluated the preclinical in\u00a0vitro and in\u00a0vivo efficacy of avutometinib, a RAF\/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS\u20104718, against multiple primary EAC cell lines and xenografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole\u2010exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in\u00a0vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in\u00a0vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS\u20104718, or their combination through oral gavage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS\/MAPK pathway including KRAS\/PTEN\/PIK3CA\/BRAF\/ARID1A, potentially sensitizing to FAK and RAF\/MEK inhibition. Five out of five of the EAC cell lines demonstrated in\u00a0vitro sensitivity to FAK and\/or RAF\/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p\u2010FAK) as well as decreased p\u2010MEK and p\u2010ERK. In\u00a0vivo the combination of avutometinib\/VS\u20104718 demonstrated superior tumor growth inhibition compared to single\u2010agent treatment and controls starting at Day 9 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.02 and\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.04) in UTE10 xenografts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in\u00a0vitro and in\u00a0vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high\u2010grade EAC patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.70210","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T11:16:45Z","timestamp":1725621405000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Preclinical evaluation of avutometinib and defactinib in high\u2010grade endometrioid endometrial cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Tobias Max Philipp","family":"Hartwich","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Mansolf","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7073-2819","authenticated-orcid":false,"given":"Cem","family":"Demirkiran","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Greenman","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Bellone","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University  New Haven Connecticut 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