SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.

Gynaecological malignancies, including cervical, endometrial, ovarian, vaginal and vulval cancers, pose therapeutic challenges that contribute to this group being the third most frequent cause of cancer-related deaths globally in women. While advances have been made in both screening for cervical cancer and immunisation against human papillomavirus strains in some countries, other gynaecological cancers have not seen improvements in early screening and prevention strategies. Drugs inhibiting poly (ADP-ribose) polymerase (PARP) have been incorporated into the clinical management of homologous recombination-deficient ovarian cancers, including as maintenance therapies post-surgery; however, these constitute only around half of all ovarian cancers. Developing new therapeutic options for all gynaecological malignancies, including those that demonstrate innate or acquired resistance to standard-of-care chemotherapeutic regimens, remains a challenge. Drug repurposing, defined as the repositioning of drugs that have been approved for the treatment of specific indications to treat other conditions, demonstrates strong potential for the clinical management of gynaecological malignancies. This review highlights diverse drug repurposing approaches applied to gynaecological cancers. Examples include computational methods such as disease and drug signature matching, network or pathway mapping, genetic association studies, drug similarity networks, molecular docking, machine learning, and serendipitous clinical observations. High-throughput compound library and drug-based phenotypic screening also contribute to candidate identification. Repurposed drugs with established safety and pharmacological profiles can accelerate therapeutic discovery; however, some regulatory and industry barriers remain. Coupled with advanced patient-centred technologies, 3D tumoroids, tumour-on-a-chip, and microfluidic systems, drug repurposing strategies promise to advance personalised medicine and improve survival outcomes for women with gynaecological malignancies.

Background: Ovarian clear cell carcinoma (OCCC) is an endometriosis‐associated ovarian cancer subtype. Somatic mutations in OCCC are reported in ARID1A , PIK3CA , and the TERT promoter ( TERTp ), as well as less commonly in KRAS and TP53 among other genes. OCCC is typically resistant to standard‐of‐care chemotherapy, especially after relapse. While recent studies have seen favourable responses to immunotherapy, patients with OCCC face limited therapeutic options. Methods: With the objective of discovering new drug treatments for OCCC, we screened OCCC (RMG‐1, JHOC‐5, OV207, OVISE, OVMANA, OVTOKO, and TOV‐21G) and non‐OCCC cell lines with a commercially available epigenetic drug compound library at two concentrations. Based on specified selection criteria, drugs were sought that preferentially inhibited viability of OCCC versus non‐OCCC cells, with subsequent validation in 2D and 3D bioprinted models and exploration of a relevant signalling pathway. Results: Taken together, OCCC cell lines were more sensitive to the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib than non‐OCCC cells, with some variation in response observed between cell lines in 2D and 3D bioprinted cultures. Furthermore, ibrutinib inhibited PI3K/AKT/mTOR cell survival signalling in some but not all OCCC cell lines, suggesting that this drug functions on additional pathways. Conclusions: Ibrutinib is used clinically to treat specific B cell disorders; however, it is not currently approved to treat solid tumours. Data presented in OCCC cell lines complements clinical observations of a therapeutic response to ibrutinib in low‐grade serous ovarian cancer. Ibrutinib demonstrates potential for the treatment of certain rare subtypes of ovarian cancer and should be further investigated.