Abstract A024: A PARP-inhibitor-induced early adaptive survival response is tackled through depletion of FRA1 by brigatinib in high-grade serous ovarian carcinoma

Abstract PARP inhibitors (PARPis) are now a standard of care for high-grade serous ovarian cancer (HGSOC), but resistance to these drugs poses a significant concern, necessitating the exploration of novel treatment strategies. Here we investigated the mechanism underlying enhanced PARPi activity in HGSOC cells following treatment with brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer. Our previous work has shown that brigatinib is a dual inhibitor of tyrosine kinases FAK and EPHA2 with subsequent additive reduction in downstream PI3K/AKT and MAPK/ERK cell survival signaling. Suppression of these pathways conferred PARPi sensitivity to HGSOC cell lines and patient-derived xenograft (PDX) models, particularly in those with high FAK and EPHA2. To dissect the mechanism linking the FAK/EPHA2 – AKT/ERK pathway to PARPi synergy, we focused on proteomics approaches which revealed that FRA1—an Activator Protein 1 (AP-1) transcription factor known to be downstream of AKT/ERK—and its targets were decreased by brigatinib treatment. In subsequent phosphoproteomics approaches and cell-based confirmatory studies, a phosphorylation crucial for FRA1 stability was found to be disrupted, leading to reduction in total FRA1 protein levels and synergy with PARPis. To explore how FRA1 mediates response to PARPis, immunoblotting analysis revealed that PARPis increased the abundance of FRA1 in HGSOC cells at early timepoints, indicating potential involvement in an adaptive survival response. Follow-up pharmacologic and gene silencing techniques demonstrated that brigatinib still reduces FRA1 in PARPi-treated cells, and FRA1 depletion induces apoptosis when combined with PARPi to levels comparable to brigatinib treatment. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy through disruption of a PARPi-induced adaptive survival mechanism. Citation Format: Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, Arun Kanakkanthara. A PARP-inhibitor-induced early adaptive survival response is tackled through depletion of FRA1 by brigatinib in high-grade serous ovarian carcinoma [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 A024.