Journal Article

Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma

Dankó, Titanilla, Vida, Ramóna, Deák, Andrea, Dezső, Katalin, Tóth, Erika, Surguta, Sára Eszter, Sebestyén, Anna, Szabó, Borbála, Krokker, Lilla, Sztankovics, Dániel, Tóvári, József, Báthory-Fülöp, László, Pongor, Lőrinc, Likó, István, Fekete, Fanni, Mészáros, Katalin, Butz, Henriett, Igaz, Péter, Patócs, Attila

2025

Overview

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.

• Publisher: MDPI AG
• Subject: Adrenal Cortex Neoplasms - drug therapy / Adrenal Cortex Neoplasms - genetics / Adrenal Cortex Neoplasms - metabolism / Adrenal Cortex Neoplasms - pathology / Adrenocortical Carcinoma - drug therapy / Adrenocortical Carcinoma - genetics / Adrenocortical Carcinoma - metabolism / Adrenocortical Carcinoma - pathology / Animals / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Cancer / Cancer therapies / Carcinoma / Care and treatment / Cell adhesion & migration / Cell growth / Cell Line, Tumor / Clinical trials / Corticosteroids / Development and progression / DNA methylation / Drug approval / Female / Focal Adhesion Kinase 1 - genetics / Focal Adhesion Kinase 1 - metabolism / Gene amplification / Gene Expression Regulation, Neoplastic - drug effects / Hormones / Humans / Immunotherapy / Kinases / Medical prognosis / Mesothelioma / Metastasis / Mice / Mitotane / Mitotane - administration & dosage / Mitotane - pharmacology / Mitotane - therapeutic use / Ovarian cancer / Steroids / Toxicity / Tumorigenesis / Tumors / Xenograft Model Antitumor Assays