{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T07:15:10Z","timestamp":1783062910878,"version":"3.54.6"},"reference-count":47,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015724","name":"Center for Cell Signaling in Gastroenterology, Mayo Clinic","doi-asserted-by":"publisher","award":["P30DK084567"],"award-info":[{"award-number":["P30DK084567"]}],"id":[{"id":"10.13039\/100015724","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Open Bio"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:p>\n                    Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer\u2010related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins. CA3 is a small\u2010molecule YAP\u2010TEAD disrupter discovered utilizing a TEAD reporter assay. Utilizing CCA, gastric cancer cell lines, and patient\u2010derived xenograft models (PDX), we demonstrate that CA3 is effective in inducing cell death and delaying tumor growth in both\n                    <jats:italic>FGFR2<\/jats:italic>\n                    fusion and wild\u2010type models. CA3 was associated with on\u2010target decreases in YAP\u2010TEAD target gene expression, TEAD reporter activity, and overall TEAD levels. Hippo pathway signaling was not altered as there was no change in YAP phosphorylation status in the cells exposed to CA3. RNA sequencing of gastric cancer and CCA models demonstrated upregulation of an androgen receptor\u2013mediated transcriptional program following exposure to CA3 in five unique models tested. Consistent with this upstream regulator analysis, CA3 exposure in CCA cells was associated with increased AR protein levels, and combinatorial therapy with CA3 and androgen receptor blockade was associated with increased cancer cell death. CA3 behaves functionally as a YAP\u2010TEAD disrupter in the models tested and demonstrated therapeutic efficacy. Exposure to CA3 was associated with compensatory androgen receptor signaling and dual inhibition improved the therapeutic effect.\n                  <\/jats:p>","DOI":"10.1002\/2211-5463.13901","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T23:34:15Z","timestamp":1726788855000},"page":"1873-1887","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>YAP<\/scp>\n                    \u2010\n                    <scp>TEAD<\/scp>\n                    inhibition is associated with upregulation of an androgen receptor mediated transcription program providing therapeutic escape"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9796-8098","authenticated-orcid":false,"given":"Roberto","family":"Alva\u2010Ruiz","sequence":"first","affiliation":[{"name":"Division of Hepatobiliary &amp; Pancreas Surgery, Department of Surgery Mayo Clinic  Rochester MN 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