Abstract A042: Targeting a cancer-specific mitotic vulnerability in ovarian cancer by combining Mirvetuximab soravtansine with inhibitors of Polo-like kinase 1

Abstract The antibody-drug conjugate (ADC) Mirvetuximab soravtansine (Mirv) has emerged as a powerful tool for suppressing and delaying the progression of epithelial ovarian cancer, including high-grade serous ovarian cancer (HGSOC). This ADC targets ovarian cancer cells based on their elevated expression of the folate receptor alpha (FRα) and, upon internalization, delivers a potent microtubule (MT) polymerization inhibitor (DM4). Mirv, however, is approved only for patients with high FRα expression and the durability of the response is finite as a consequence of drug resistance. We discovered that inhibitors of Polo-like kinase 1 (Plk1), a critical mitotic kinase, synergistically kill a variety of tumor cell types, including many HGSOC cell lines, when combined with microtubule polymerization inhibitors, including DM4 the payload of Mirv. This synergistic tumor cell death results from a cancer cell-specific mitotic vulnerability, leading to drug combination-specific mitotic spindle defects that cause mitotic arrest and subsequent spindle assembly checkpoint-dependent cell death. The efficacy of this synergistic drug combination was further validated in human patient-derived HGSOC organoids, and in an in vivo human HGSOC murine xenograft model. To elucidate the molecular mechanism underlying this Plk1i/anti-microtubule drug synergy, we performed a genome-wide CRISPR-A screen, implicating specific molecular components of the kinetochore (KT) as the targets responsible for synergistic killing. To further validate this molecular mechanism, we report here that this drug combination potently disrupts KT-MT attachments due to the loss of Plk1-dependent kinetochore protein phosphorylation required for optimal MT capture. These data are consistent with a model in which inhibition of Plk1 activity compromises KT function, rendering cancer cells hyper-reliant on MT dynamics to achieve the proper KT-MT attachments that are essential for accurate chromosome segregation. Our work indicates that targeting Plk1 could enhance and extend the durability of clinical response in HGSOC patients treated with Mirv and possibly expand the utility of Mirv to patients with lower FRα expression. To translate these findings into the clinic, we have acquired funding to support an investigator-sponsored phase 1 clinical trial testing this combination in ovarian cancer patients through the MIT — Dana-Farber/Harvard Cancer Center Bridge Program. This trial utilizes the ADC Mirv, currently FDA approved for ovarian cancer treatment, in combination with the Plk1 inhibitor Onvansertib, which has been used in multiple prior and ongoing clinical trials with an established safety profile. The trial will recruit patients planning to initiate Mirv with the addition of Onvansertib, using a BOIN dose escalation strategy. The primary endpoint is safety with secondary endpoints assessing radiographic responses and molecular correlations of any clinical responses. Citation Format: Jesse C. Patterson, Nabihah Tayob, Robin Lu, Yi Wen Kong, Brian A. Joughin, Eugene Kim, Bo Rueda, Joyce F. Liu, Ursula A. Matulonis, Meghan Shea, Michael B. Yaffe. Targeting a cancer-specific mitotic vulnerability in ovarian cancer by combining Mirvetuximab soravtansine with inhibitors of Polo-like kinase 1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A042.