{"doi":"10.3390/ijms26136539","title":"Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma","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—drug 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>","journal":"International Journal of Molecular Sciences","year":2025,"id":633695,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1643121,"name":"Lőrinc Pongor","orcid":null,"position":1,"is_corresponding":false},{"id":1643122,"name":"Lilla Krokker","orcid":null,"position":2,"is_corresponding":false},{"id":1643124,"name":"Borbála Szabó","orcid":null,"position":3,"is_corresponding":false},{"id":1637431,"name":"Katalin Dezső","orcid":"0000-0002-4856-0483","position":4,"is_corresponding":false},{"id":1643125,"name":"Titanilla Dankó","orcid":null,"position":5,"is_corresponding":false},{"id":376272,"name":"Anna Sebestyén","orcid":"0000-0001-8814-4794","position":6,"is_corresponding":false},{"id":1643126,"name":"Dániel Sztankovics","orcid":"0009-0007-3168-1151","position":7,"is_corresponding":false},{"id":1643127,"name":"József Tóvári","orcid":"0000-0002-5543-3204","position":8,"is_corresponding":false},{"id":1643128,"name":"Sára Eszter Surguta","orcid":null,"position":9,"is_corresponding":false},{"id":376264,"name":"István Likó","orcid":"0000-0001-7668-4726","position":10,"is_corresponding":false},{"id":376266,"name":"Katalin Mészáros","orcid":"0000-0002-1002-1089","position":11,"is_corresponding":false},{"id":1643129,"name":"Andrea Deák","orcid":"0000-0001-7988-0255","position":12,"is_corresponding":false},{"id":1643130,"name":"Fanni Fekete","orcid":null,"position":13,"is_corresponding":false},{"id":1643131,"name":"Ramóna Vida","orcid":"0009-0006-4902-8663","position":14,"is_corresponding":false},{"id":1643132,"name":"László Báthory-Fülöp","orcid":null,"position":15,"is_corresponding":false},{"id":1643133,"name":"Erika Tóth","orcid":"0000-0003-2054-8447","position":16,"is_corresponding":false},{"id":724644,"name":"Péter Igaz","orcid":"0000-0003-2192-554X","position":17,"is_corresponding":false},{"id":376273,"name":"Attila Patócs","orcid":"0000-0001-7506-674X","position":18,"is_corresponding":false},{"id":1330550,"name":"Henriett Butz","orcid":"0000-0003-1664-409X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma","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—drug 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>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40650315","pmcid":"PMC12249900","openalex_id":null,"authors":[],"funders":[{"funder_name":"Hungarian Scientific Research Grant of the National Research, Development and Innovation (NRDI) Office Fund of the Ministry of Culture and Innovation under the National Laboratories Program (National Tumour Biology Laboratory","grant_id":"2022-2.1.1-NL-2022-00010","title":null},{"funder_name":"Hungarian Scientific Research Grant of the National Research, Development and Innovation (NRDI) Office Fund of the Ministry of Culture and Innovation under the National Laboratories Program (National Tumour Biology Laboratory","grant_id":"TKP2021-EGA/TKP2021-NVA/TKP2021-NKTA, MOLORKIV","title":null},{"funder_name":"Hungarian Scientific Research Grant of the National Research, Development and Innovation (NRDI) Office Fund of the Ministry of Culture and Innovation under the National Laboratories Program (National Tumour Biology Laboratory","grant_id":"NRDI NKFI-FK135065","title":null},{"funder_name":"Hungarian Scientific Research Grant of the National Research, Development and Innovation (NRDI) Office Fund of the Ministry of Culture and Innovation under the National Laboratories Program (National Tumour Biology Laboratory","grant_id":"ÚNKP-23-5-SE-4","title":null},{"funder_name":"Hungarian Scientific Research Grant of the National Research, Development and Innovation (NRDI) Office Fund of the Ministry of Culture and Innovation under the National Laboratories Program (National Tumour Biology Laboratory","grant_id":"BO/00092/21","title":null},{"funder_name":"European Commission","grant_id":"739593","title":"Establishing the Hungarian Center of Excellence for Molecular Medicine in partnership with EMBL"}],"total_grants":6,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/26/13/6539/pdf?version=1751895014","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/26/13/6539/pdf","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12249900","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12249900","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12249900?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.3390/ijms26136539","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/40650315","host_type":""},{"url":"http://dx.doi.org/10.3390/ijms26136539","host_type":""},{"url":"https://dx.doi.org/10.3390/ijms26136539","host_type":""}],"fields_of_study":["03 medical and health sciences","0302 clinical medicine"],"mesh_terms":["Cell Line, Tumor","Animals","Humans","Mice","Adrenocortical Carcinoma","Adrenal Cortex Neoplasms","Mitotane","Antineoplastic Combined Chemotherapy Protocols","Xenograft Model Antitumor Assays","Gene Expression Regulation, Neoplastic","Female","Focal Adhesion Kinase 1"],"keywords":["Targeted Therapy","Drug Repurposing","3d Model","Adrenocortical Cancer","Defactinib","Focal Adhesion Signalling","Xenograft Model Antitumor Assays","Article","Adrenal Cortex Neoplasms","Gene Expression Regulation, Neoplastic","Mice","Cell Line, Tumor","Focal Adhesion Kinase 1","Antineoplastic Combined Chemotherapy Protocols","Adrenocortical Carcinoma","Humans","Animals","Female","Mitotane"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"cellosaurus"},{"name":"go"},{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T12:30:51.363275Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}