Abstract 3869: Targeting anoikis resistance in ovarian cancer via metabolic enzyme inhibition

Ovarian cancer (OvCa) is the deadliest gynecologic malignancy, with poor prognosis largely due to late-stage diagnosis and metastasis, which limit treatment options and contribute to high mortality. Anoikis resistance, a key mechanism enabling metastatic spheroids to survive in the peritoneal cavity, drives both metastasis and therapy resistance. Therefore, understanding the regulation of anoikis is critical for identifying novel therapeutic targets. Recent studies, including work from our group, have identified overexpression of cystathionine beta-synthase (CBS)—an enzyme that produces hydrogen sulfide (H2S)—as a contributor to OvCa progression. CBS has been shown to promote cancer progression through enhanced lipogenesis and mitochondrial fusion. Based on these findings, we hypothesize that CBS plays a central role in anoikis resistance in OvCa and propose that targeting CBS could inhibit metastasis and improve sensitivity to chemotherapy. To investigate the functional role of CBS in anoikis resistance, we utilized OvCa cell lines (COV318, OVCAR8, OVCAR4, and A2780_CP20) and achieved CBS silencing via siRNA-mediated knockdown. Cells were cultured in both monolayers (2D) and spheroids (3D) to better mimic in vivo tumor conditions. Our findings reveal that: (i) High CBS expression is associated with poor median survival in stage 3 and stage 4 high-grade serous ovarian cancer (HGSOC) patients, (ii)CBS expression directly correlates with elevated expression of stemness and epithelial-to-mesenchymal transition (EMT) markers, (iii) CBS silencing induces anoikis in both COV318 (ascites-derived) and A2780_CP20 (drug-resistant) OvCa cell lines, (iv) CBS silencing disrupts integrin-mediated downstream signaling through focal adhesion kinase (FAK) in both 2D and 3D cultures. These findings establish CBS as a critical regulator of anoikis resistance in ovarian cancer, underscoring its potential as a therapeutic target to suppress metastasis and enhance the efficacy of existing chemotherapy regimens. Citation Format: Geeta Rao, Pallab Shaw, Shailendra Dwivedi, Priyabrata Mukherjee. Targeting anoikis resistance in ovarian cancer via metabolic enzyme inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3869.