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National Excellence Program of the Ministry of Human Capacities","award":["TKP2021-EGA\/TKP2021-NVA\/TKP2021-NKTA, MOLORKIV"],"award-info":[{"award-number":["TKP2021-EGA\/TKP2021-NVA\/TKP2021-NKTA, MOLORKIV"]}]},{"name":"New National Excellence Program of the Ministry of Human Capacities","award":["NRDI NKFI-FK135065"],"award-info":[{"award-number":["NRDI NKFI-FK135065"]}]},{"name":"New National Excellence Program of the Ministry of Human Capacities","award":["\u00daNKP-23-5-SE-4"],"award-info":[{"award-number":["\u00daNKP-23-5-SE-4"]}]},{"name":"New National Excellence Program of the Ministry of Human Capacities","award":["BO\/00092\/21"],"award-info":[{"award-number":["BO\/00092\/21"]}]},{"name":"Bolyai Research Fellowship of the Hungarian Academy of Sciences","award":["2022-2.1.1-NL-2022-00010"],"award-info":[{"award-number":["2022-2.1.1-NL-2022-00010"]}]},{"name":"Bolyai Research Fellowship of the Hungarian Academy of Sciences","award":["TKP2021-EGA\/TKP2021-NVA\/TKP2021-NKTA, MOLORKIV"],"award-info":[{"award-number":["TKP2021-EGA\/TKP2021-NVA\/TKP2021-NKTA, MOLORKIV"]}]},{"name":"Bolyai Research Fellowship of the Hungarian Academy of Sciences","award":["NRDI NKFI-FK135065"],"award-info":[{"award-number":["NRDI NKFI-FK135065"]}]},{"name":"Bolyai Research Fellowship of the Hungarian Academy of Sciences","award":["\u00daNKP-23-5-SE-4"],"award-info":[{"award-number":["\u00daNKP-23-5-SE-4"]}]},{"name":"Bolyai Research Fellowship of the Hungarian Academy of Sciences","award":["BO\/00092\/21"],"award-info":[{"award-number":["BO\/00092\/21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter of ongoing clinical debate. Drug repurposing is a cost-effective way to identify new therapies, and defactinib, currently in clinical trials as part of combination therapies for various solid tumours, may enhance ACC treatment. We aimed to assess its efficacy in combination with mitotane. We tested the combination of mitotane and defactinib in H295R, SW13, and mitotane-sensitive and -resistant HAC15 cells, using functional assays, transcriptomic profiling, 2D and 3D cultures, bioprinted tissues, and xenografts. We assessed drug interactions with NMR and toxicity in vivo, as mitotane and defactinib have never been previously administered together. Genomic data from 228 human ACC and 158 normal adrenal samples were also analysed. Transcriptomic analysis revealed dysregulation of focal adhesion along with mitotane-related pathways. Focal adhesion kinase (FAK) signalling was enhanced in ACC compared to normal adrenal glands, with PTK2 (encoding FAK) upregulated in 44% of tumour samples due to copy number alterations. High FAK signature scores correlated with worse survival outcomes. FAK inhibition by defactinib, both alone and in combination with mitotane, showed effective anti-tumour activity in vitro. No toxicity or drug\u2014drug interactions were observed in vivo. Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation.<\/jats:p>","DOI":"10.3390\/ijms26136539","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T10:03:27Z","timestamp":1751882607000},"page":"6539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1664-409X","authenticated-orcid":false,"given":"Henriett","family":"Butz","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and the National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"},{"name":"Department of Oncology Biobank, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"},{"name":"Department of Laboratory Medicine, Semmelweis University, 4 Nagyvarad ter, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u0151rinc","family":"Pongor","sequence":"additional","affiliation":[{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"},{"name":"Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine, 9 Budapesti ut, H-6728 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilla","family":"Krokker","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Semmelweis University, 4 Nagyvarad ter, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borb\u00e1la","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Semmelweis University, 4 Nagyvarad ter, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katalin","family":"Dezs\u0151","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Cancer Research, Semmelweis University, 26. Ulloi ut, H-1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Titanilla","family":"Dank\u00f3","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Cancer Research, Semmelweis University, 26. Ulloi ut, H-1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Sebesty\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Cancer Research, Semmelweis University, 26. Ulloi ut, H-1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3168-1151","authenticated-orcid":false,"given":"D\u00e1niel","family":"Sztankovics","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Cancer Research, Semmelweis University, 26. Ulloi ut, H-1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5543-3204","authenticated-orcid":false,"given":"J\u00f3zsef","family":"T\u00f3v\u00e1ri","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and the National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e1ra Eszter","family":"Surguta","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and the National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Istv\u00e1n","family":"Lik\u00f3","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and the National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katalin","family":"M\u00e9sz\u00e1ros","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Semmelweis University, 4 Nagyvarad ter, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7988-0255","authenticated-orcid":false,"given":"Andrea","family":"De\u00e1k","sequence":"additional","affiliation":[{"name":"Artificial Transporter Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, 2 Magyar Tudosok korutja, H-1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanni","family":"Fekete","sequence":"additional","affiliation":[{"name":"Department of Oncology Biobank, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4902-8663","authenticated-orcid":false,"given":"Ram\u00f3na","family":"Vida","sequence":"additional","affiliation":[{"name":"Department of Oncology Biobank, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e1szl\u00f3","family":"B\u00e1thory-F\u00fcl\u00f6p","sequence":"additional","affiliation":[{"name":"Department of Surgical and Molecular Pathology and the National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2054-8447","authenticated-orcid":false,"given":"Erika","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Department of Surgical and Molecular Pathology and the National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2192-554X","authenticated-orcid":false,"given":"P\u00e9ter","family":"Igaz","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Faculty of Medicine, Semmelweis University, 26. Ulloi ut, H-1085 Budapest, Hungary"},{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 2 Koranyi Sandor, utca, H-1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7506-674X","authenticated-orcid":false,"given":"Attila","family":"Pat\u00f3cs","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and the National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 7-9 Rath Gyorgy utca, H-1122 Budapest, Hungary"},{"name":"Department of Laboratory Medicine, Semmelweis University, 4 Nagyvarad ter, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1016\/j.annonc.2020.08.2099","article-title":"Adrenocortical Carcinomas and Malignant Phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up","volume":"31","author":"Fassnacht","year":"2020","journal-title":"Ann. 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