Abstract IA006: Targeting replication stress and cell-cycle checkpoints to overcome CIC-rearranged sarcomas

Abstract Capicua (CIC) rearranged sarcomas are a rare but lethal group of soft-tissue sarcomas most commonly found in pediatric and adolescence and young adults (AYA). The most well-characterized CIC-rearrangement is the prototypical CIC::DUX4 fusion oncoprotein, which currently has no effective therapies and is associated with dismal clinical outcomes. Using rare patient-derived CIC::DUX4 cells we recently identified a molecular dependence on the CCNE/CDK2 complex in CIC::DUX4 sarcoma, whereby the CIC::DUX4 oncoprotein transcriptionally upregulates CCNE1 to drive sarcoma growth and survival. Mechanistically, increased CCNE1expression through transcriptional upregulation compromises the G1/S transition to enhance DNA replication stress and genomic instability. Cancer cells adapt to these high replication stress states through increased dependence on cell-cycle checkpoints that enable replication stalling and DNA repair. Consistent with this, we recently defined the G2/M checkpoint kinase, WEE1 as a key regulator of mitotic entry and survival in CIC::DUX4 sarcomas. WEE1 inhibition releases the G2/M break and allows premature mitotic entry and subsequent death through irreversible DNA damage and mitotic catastrophe. We will discuss strategies to pharmacologically exploit this CCNE1 mediated high replication stress state through combinatorial drug approaches that augment replication stress and/or co-target the G2/M checkpoint in CIC-rearranged cancers. Citation Format: Ross A. Okimoto, Padmini Bisoyi, Rovingaile Kriska Ponce, Nicholas Thomas. Targeting replication stress and cell-cycle checkpoints to overcome CIC-rearranged sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr IA006.