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Inhibitors of ERK1\/2 signalling used for cancer are cardiotoxic in some patients, raising the question of whether dabrafenib is cardiotoxic. In the heart, ERK1\/2 signalling promotes not only cardiomyocyte hypertrophy and is cardioprotective but also promotes fibrosis. Our hypothesis is that ERK1\/2 signalling is not required in a non-stressed heart but is required for cardiac remodelling. Thus, dabrafenib may affect the heart in the context of, for example, hypertension. In experiments with cardiomyocytes, cardiac fibroblasts and perfused rat hearts, dabrafenib inhibited ERK1\/2 signalling. We assessed the effects of dabrafenib (3 mg\/kg\/d) on male C57BL\/6J mouse hearts in vivo. Dabrafenib alone had no overt effects on cardiac function\/dimensions (assessed by echocardiography) or cardiac architecture. In mice treated with 0.8 mg\/kg\/d angiotensin II (AngII) to induce hypertension, dabrafenib inhibited ERK1\/2 signalling and suppressed cardiac hypertrophy in both acute (up to 7 d) and chronic (28 d) settings, preserving ejection fraction. At the cellular level, dabrafenib inhibited AngII-induced cardiomyocyte hypertrophy, reduced expression of hypertrophic gene markers and almost completely eliminated the increase in cardiac fibrosis both in interstitial and perivascular regions. Dabrafenib is not overtly cardiotoxic. Moreover, it inhibits maladaptive hypertrophy resulting from AngII-induced hypertension. Thus, Raf is a potential therapeutic target for hypertensive heart disease and drugs such as dabrafenib, developed for cancer, may be used for this purpose.<\/jats:p>","DOI":"10.1042\/cs20210192","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T10:10:41Z","timestamp":1627035041000},"page":"1631-1647","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension"],"prefix":"10.1042","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5557-3549","authenticated-orcid":false,"given":"Daniel N.","family":"Meijles","sequence":"first","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."},{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Cull","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna T.E.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomais","family":"Markou","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle A.","family":"Hardyman","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Fuller","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajed O.","family":"Alharbi","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe H.R.","family":"Haines","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viridiana","family":"Alcantara-Alonso","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter E.","family":"Glennon","sequence":"additional","affiliation":[{"name":"University Hospitals Coventry and Warwickshire, University Hospital Cardiology Department, Clifford Bridge Road, Coventry CV2 2DX, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary N.","family":"Sheppard","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St George\u2019s University of London, London SW17 0RE, U.K."},{"name":"CRY Cardiovascular Pathology Department, St. George's University of London, London, U.K."},{"name":"St. George\u2019s Healthcare NHS Trust, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H.","family":"Sugden","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5658-0708","authenticated-orcid":false,"given":"Angela","family":"Clerk","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Reading, Reading RG6 2AS, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"2021113011221392700_B1","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/s41580-020-0255-7","article-title":"ERK signalling: a master regulator of cell behaviour, life and fate","volume":"21","author":"Lavoie","year":"2020","journal-title":"Nat. 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