{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:48:42Z","timestamp":1775753322320,"version":"3.50.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Medical Research Center Initiative for High Depth Omics (Science Tokyo), Nanken-Kyoten (Science Tokyo), and Multilayered Stress Diseases"},{"name":"Foundation for Promotion of Cancer Research in Japan"},{"DOI":"10.13039\/501100008886","name":"Princess Takamatsu Cancer Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008886","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007533","name":"Kobayashi Foundation for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007533","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Science and Technology Agency (JST) FOREST Program","award":["JPMJFR226J"],"award-info":[{"award-number":["JPMJFR226J"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI grants","award":["24H00864 and 24H00865"],"award-info":[{"award-number":["24H00864 and 24H00865"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The Hippo pathway, traditionally recognized for its tumor suppressive function, has been paradoxically implicated in promoting tumor progression in cancers, such as estrogen receptor-positive breast cancer. Treatment of ER-positive breast cancer faces notable challenges owing to the growing incidence of tumor resistance to hormonal therapies, highlighting the need for alternative therapeutic strategies. Here, we explored potential Hippo pathway inhibitors through the multistep screening of 1150 kinase inhibitors and identified GSK690693 as a potent inhibitor of the Hippo pathway, specifically targeting LATS1 kinase activity. GSK690693 effectively downregulated ER expression in MCF-7 breast cancer cells by suppressing the Hippo pathway activity. Mechanistically, treatment with GSK690693 led to cell cycle arrest and induction of cell death. These findings revealed a previously undefined mechanism of action of GSK690693 as a Hippo pathway inhibitor, underscoring its efficacy in mitigating ER-positive breast cancer progression. Given the broader implications of Hippo pathway dysregulation in multiple cancers, GSK690693 could be part of a combination regimen for various malignancies.<\/jats:p>","DOI":"10.1093\/jb\/mvag005","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T12:18:31Z","timestamp":1768220311000},"page":"283-292","source":"Crossref","is-referenced-by-count":0,"title":["A kinase inhibitor screen identifies GSK690693 as a Hippo pathway inhibitor targeting ER-positive breast cancer"],"prefix":"10.1093","volume":"179","author":[{"given":"Haruka","family":"Kurata","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Kumamoto 860-8556 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samson","family":"Ngurari","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Kumamoto 860-8556 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Nita","sequence":"additional","affiliation":[{"name":"Division of Cellular Dynamics, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo , 1-5-45 Yushima, Tokyo 113-8510 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhisa","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Kumamoto 860-8556 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Nduru","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Kumamoto 860-8556 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6419-3882","authenticated-orcid":false,"given":"Toshiro","family":"Moroishi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Kumamoto 860-8556 ,","place":["Japan"]},{"name":"Division of Cellular Dynamics, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo , 1-5-45 Yushima, Tokyo 113-8510 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"2026040911514872800_ref1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s41232-024-00331-8","article-title":"Hippo pathway in cell-cell communication: emerging roles in development and regeneration","volume":"44","author":"Nita","year":"2024","journal-title":"Inflamm Regen"},{"key":"2026040911514872800_ref2","article-title":"Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential","volume":"4","author":"Lv","year":"2023","journal-title":"MedComm (2020)"},{"key":"2026040911514872800_ref3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/cas.14725","article-title":"The role of Hippo-YAP signaling in squamous cell carcinomas","volume":"112","author":"Maehama","year":"2021","journal-title":"Cancer Sci."},{"key":"2026040911514872800_ref4","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2024.113926","article-title":"The Hippo signaling pathway in development and regeneration","volume":"43","author":"Zhong","year":"2024","journal-title":"Cell Rep."},{"key":"2026040911514872800_ref5","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.cell.2015.10.044","article-title":"Hippo pathway in organ size control, tissue homeostasis, and cancer","volume":"163","author":"Yu","year":"2015","journal-title":"Cell"},{"key":"2026040911514872800_ref6","doi-asserted-by":"crossref","first-page":"600","DOI":"10.3390\/cells8060600","article-title":"Regulation of TEAD transcription factors in cancer biology","volume":"8","author":"Huh","year":"2019","journal-title":"Cells"},{"key":"2026040911514872800_ref7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nrc3876","article-title":"The emerging roles of YAP and TAZ in cancer","volume":"15","author":"Moroishi","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"2026040911514872800_ref8","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s12967-019-1869-4","article-title":"Analysis of the role of the Hippo pathway in cancer","volume":"17","author":"Han","year":"2019","journal-title":"J. Transl. Med."},{"key":"2026040911514872800_ref9","doi-asserted-by":"crossref","first-page":"2700","DOI":"10.1038\/s41467-024-46531-1","article-title":"Expected and unexpected effects after systemic inhibition of Hippo transcriptional output in cancer","volume":"15","author":"Baroja","year":"2024","journal-title":"Nat. Commun."},{"key":"2026040911514872800_ref10","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1038\/s41586-020-03131-5","article-title":"Hippo signalling maintains ER expression and ER(+) breast cancer growth","volume":"591","author":"Ma","year":"2021","journal-title":"Nature"},{"key":"2026040911514872800_ref11","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1038\/s41467-022-30831-5","article-title":"YAP inhibits ERalpha and ER(+) breast cancer growth by disrupting a TEAD-ERalpha signaling axis","volume":"13","author":"Li","year":"2022","journal-title":"Nat. Commun."},{"key":"2026040911514872800_ref12","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/s41467-022-28691-0","article-title":"Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER(+) breast cancer","volume":"13","author":"Ma","year":"2022","journal-title":"Nat. Commun."},{"key":"2026040911514872800_ref13","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.21873\/anticanres.14486","article-title":"The future of ER+\/HER2- metastatic breast cancer therapy: beyond PI3K inhibitors","volume":"40","author":"Stravodimou","year":"2020","journal-title":"Anticancer Res."},{"key":"2026040911514872800_ref14","doi-asserted-by":"crossref","first-page":"1758835920940939","DOI":"10.1177\/1758835920940939","article-title":"Targeting the PI3K\/Akt\/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer","volume":"12","author":"Rusquec","year":"2020","journal-title":"Ther Adv Med Oncol"},{"key":"2026040911514872800_ref15","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1159\/000508675","article-title":"Endocrine-resistant breast cancer: mechanisms and treatment","volume":"15","author":"Hartkopf","year":"2020","journal-title":"Breast Care (Basel)"},{"key":"2026040911514872800_ref16","doi-asserted-by":"crossref","first-page":"11230","DOI":"10.1074\/jbc.RA118.002715","article-title":"The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell","volume":"293","author":"Plouffe","year":"2018","journal-title":"J. Biol. Chem."},{"key":"2026040911514872800_ref17","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.cell.2016.11.005","article-title":"The Hippo pathway kinases LATS1\/2 suppress cancer immunity","volume":"167","author":"Moroishi","year":"2016","journal-title":"Cell"},{"key":"2026040911514872800_ref18","doi-asserted-by":"crossref","DOI":"10.1016\/j.jprot.2022.104582","article-title":"Phosphorylation analysis of the Hippo-YAP pathway using Phos-tag","volume":"261","author":"Kim","year":"2022","journal-title":"J. Proteome"},{"key":"2026040911514872800_ref19","doi-asserted-by":"crossref","first-page":"8357","DOI":"10.1038\/ncomms9357","article-title":"MAP4K family kinases act in parallel to MST1\/2 to activate LATS1\/2 in the Hippo pathway","volume":"6","author":"Meng","year":"2015","journal-title":"Nat. Commun."},{"key":"2026040911514872800_ref20","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/s41392-022-01191-9","article-title":"The Hippo signalling pathway and its implications in human health and diseases","volume":"7","author":"Fu","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"2026040911514872800_ref21","first-page":"3147","article-title":"The story of MCF-7 breast cancer cell line: 40 years of experience in research","volume":"35","author":"Comsa","year":"2015","journal-title":"Anticancer Res."},{"key":"2026040911514872800_ref22","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/febs.12658","article-title":"Estrogen receptor alpha mediates proliferation of breast cancer MCF-7 cells via a p21\/PCNA\/E2F1-dependent pathway","volume":"281","author":"Liao","year":"2014","journal-title":"FEBS J."},{"key":"2026040911514872800_ref23","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1158\/1078-0432.CCR-09-1026","article-title":"GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt","volume":"16","author":"Altomare","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"2026040911514872800_ref24","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3000509","article-title":"The Hippo pathway integrates PI3K-Akt signals with mechanical and polarity cues to control tissue growth","volume":"17","author":"Borreguero-Munoz","year":"2019","journal-title":"PLoS Biol."},{"key":"2026040911514872800_ref25","doi-asserted-by":"crossref","first-page":"493","DOI":"10.4196\/kjpp.2023.27.5.493","article-title":"Inhibition of the interaction between Hippo\/YAP and Akt signaling with ursolic acid and 3\u20323-diindolylmethane suppresses esophageal cancer tumorigenesis","volume":"27","author":"Meng","year":"2023","journal-title":"Korean J Physiol Pharmacol"},{"key":"2026040911514872800_ref26","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3390\/biomedicines11010109","article-title":"Targeting PI3K\/AKT\/mTOR pathway in breast cancer: from biology to clinical challenges","volume":"11","author":"Cerma","year":"2023","journal-title":"Biomedicines"},{"key":"2026040911514872800_ref27","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1182\/blood-2008-02-137737","article-title":"AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines","volume":"113","author":"Levy","year":"2009","journal-title":"Blood"},{"key":"2026040911514872800_ref28","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.ccell.2021.06.016","article-title":"Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP\/TEAD activity","volume":"39","author":"Pearson","year":"2021","journal-title":"Cancer Cell"},{"key":"2026040911514872800_ref29","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1083\/jcb.201501025","article-title":"Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway","volume":"210","author":"Kim","year":"2015","journal-title":"J. Cell Biol."},{"key":"2026040911514872800_ref30","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1158\/0008-5472.CAN-20-2801","article-title":"YAP and beta-catenin cooperate to drive oncogenesis in basal breast cancer","volume":"81","author":"Quinn","year":"2021","journal-title":"Cancer Res."}],"container-title":["The Journal of Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jb\/advance-article-pdf\/doi\/10.1093\/jb\/mvag005\/66386789\/mvag005.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jb\/article-pdf\/179\/4\/283\/66386789\/mvag005.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jb\/article-pdf\/179\/4\/283\/66386789\/mvag005.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T15:51:59Z","timestamp":1775749919000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jb\/article\/179\/4\/283\/8424061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,13]]},"references-count":30,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,1,13]]},"published-print":{"date-parts":[[2026,4,13]]}},"URL":"https:\/\/doi.org\/10.1093\/jb\/mvag005","relation":{},"ISSN":["0021-924X","1756-2651"],"issn-type":[{"value":"0021-924X","type":"print"},{"value":"1756-2651","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2026,1,13]]}}}