Abstract A015: Unlocking therapeutic potential of rigosertib as a selective therapy for ovarian cancer

Abstract Ovarian cancer has a devastating impact. In 2024 it is estimated that there will be 19,680 new ovarian cancer diagnoses and 12,740 fatalities in the United States. Despite advancements in treatment options, 80% of ovarian tumors recur or progress through treatments leading to a five year survival rate of just 50%. To address this unmet need, we employed a functional genomics approach to identify ovarian cancer specific drug sensitivities. Comparing the impact of each of the 117 drugs in our library across 32 cancer cell lines from 11 tumor lineages we identified Rigosertib, a small molecule RAS mimetic, as a selective agent for treatment of ovarian cancer. This ovarian cancer specific sensitivity to Rigosertib was validated in a panel of ovarian cancer cell lines and patient-derived organoids. This sensitivity fits with the observation that ovarian cancer exhibits a high frequency of alterations in both the PI3K and MAPK pathways, both of which can be negatively regulated through the disruption of RAS interactions. Concordantly, while the interplay between these pathways creates an inverse regulatory relationship by which inhibition of either pathway can lead to activation of the other, we observe that in all of the ovarian lines tested that treatment with Rigosertib leads to increases of MTOR signaling as indicated by phosphorylation of S6 both in vitro and in vivo. Subsequent combination drug screening revealed a cooperative effect between rigosertib and PI3K inhibitor (taselisib), suggesting that combining rigosertib with taselisib which restricts mTOR activation enhances therapeutic efficacy. This combination showed synergy across ovarian cancer cell lines, organoids, and xenograft models, with xenograft studies showing a significant reduction in tumor burden. These findings highlight the potential of rigosertib, especially when paired with PI3K inhibitors, to target the unique mutational landscape of ovarian cancer, offering a promising direction for more effective treatments. Citation Format: SHALINI NATH, Sally Claridge, Genesis Lara Granados, Majd Al Assaad, Eric Park, Julie-Ann Cavallo, Maame Esi Ackon, Lamberto De Boni, Stacey Baker, E. Premkumar Reddy, Stephanie V Blank, Olivier Elemento, Rachel Brody, Benjamin D. Hopkins. Unlocking therapeutic potential of rigosertib as a selective therapy for ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A015.