Abstract 7034: The impact of EphA2 in the malignancy of CIC-DUX sarcomas

Abstract Capicua (CIC)-rearranged sarcomas (CDS) are rare and highly aggressive undifferentiated small round cell sarcomas and patients with CDS have a dismal prognosis. Despite being recognized as a distinct entity by WHO 2020, these tumors are still treated according to Ewing sarcoma regimens and new more specific treatment options are urgently needed. Previous work, including data from our group, has identified the IGF-AKT-mTOR signaling pathway as particularly active in these tumors. Here, we highlight the role of the Ephrin system, particularly the EphA2 receptor, in CDS. EphA2-mediated signaling emerged from a core set of 71 genes that clearly distinguish CDS from Ewing sarcoma (PMID: 34903601). Functional studies on three CDS cell lines obtained from patient-derived xenografts (PDX) confirmed the high expression of the receptor, which was constitutively activated on serine residue 897 (S897). EphA2 is highly expressed in embryos during development, declines in later stages and can be re-expressed in cancer. EphA2 is implicated in self-renewal, chemoresistance, and metastasis and its expression correlate with poor patient outcome in several tumors (PMID:33686241). The targeting of EphA2 is thus under investigation. However, EphA2 signaling is complex, occurring through canonical, ligand-dependent mechanisms and/or non-canonical ones mediated by crosstalk with other receptors, kinases or activated by different ligands. In CDS, AKT is hyper-active due to the constitutive activation of IGF2/IGF1R signaling and the intrinsic inhibition of MAPK. AKT induces strong phosphorylation of EphA2 at S897, which leads to a conformational change of EphA2, promoting cell migration and metastasis. This mechanism renders CDS cells resistant to traditional anti-EphA2 tyrosine kinase (TK) inhibitors used as single agents. Therefore, we have successfully tested the efficacy of a combination between ALW-II-41-27, a widely used inhibitor of EphA2 kinase activity, and IGF-1R/AKT inhibitors in preclinical models. In addition, we are testing EphA2 targeted degradation by using HaloPROTAC3 approaches to confirm the impact of targeting EphA2 on CDS cell migration and metastasis. The research leading to these results has received funding from AIRC under IG 2019—ID. 22805 project—P.I. K. Scotlandi. For HaloPROTAC studies support was provided by the Italian Ministry of Health through the Executive Programme of Cooperation in the field of Science and Technology between Italy and the USA 2023-2025, MAECI-2023-23683465, to C. Mancarella. Citation Format: Lisa Toracchio, Alberto Bavelloni, Caterina Mancarella, Lorena Landuzzi, Andrea Morini, Elisa Simonetti, Pier Luigi Lollini, Andrea Morrione, Katia Scotlandi. The impact of EphA2 in the malignancy of CIC-DUX sarcomas [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 7034.