Co-targeting CDK2 and CDK9 inhibits MYC oncogenic programs and has anti-tumor effects in CIC-rearranged sarcoma

Abstract Background CIC -rearranged sarcoma is a rare and highly aggressive cancer that primarily affects children and young adults and has few effective treatment options. Previous studies have identified molecular dependence on cyclin-dependent kinase 2 (CDK2), but additional therapeutic vulnerabilities remain poorly defined. Here, we investigate the activity of CDK2-targeted therapies and evaluate combination strategies using new patient-derived models of CIC -rearranged sarcoma. Methods We established patient-derived cell lines and matching xenograft models from tumors harboring CIC::DUX4 and CIC::NUTM1 fusions, with xenograft studies performed in 7-week-old female NSG mice. We assessed the effects of CDK2 inhibition alone and in combination with cyclin-dependent kinase 9 (CDK9) inhibition using molecular, functional, and transcriptomic analyses in vitro and in vivo. Results Here we show that CIC -rearranged sarcoma depends on the MYC oncogene and is vulnerable to CDK2 inhibition. The CDK2 inhibitor tagtociclib suppresses MYC-regulated gene expression, inhibits tumor cell proliferation, and reduces tumor growth in patient-derived models. Combined inhibition of CDK2 and CDK9 produces synergistic anti-tumor activity by further suppressing MYC-driven transcription, enhancing apoptotic cell death, and improving tumor control in vitro and in vivo. Conclusions These findings identify MYC-driven transcription as a therapeutic vulnerability in CIC -rearranged sarcoma and support combined CDK2 and CDK9 inhibition as a promising treatment strategy. The patient-derived models established in this study also provide valuable resources for future preclinical and translational research.