Epigenetic Compound Library Screen Identifies Ibrutinib as an Inhibitor of Ovarian Clear Cell Carcinoma Viability

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.