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

CIC-rearranged sarcoma is an aggressive mesenchymal neoplasm characterized by capicua (CIC) gene rearrangement and molecular dependence on the CDK2-cyclin E complex. Given its high metastatic potential and poor clinical outcomes, there is an urgent need to identify biologic vulnerabilities for therapeutic targeting. Here, we determined the efficacy of CDK2-targeted therapies in preclinical models of CIC- rearranged sarcoma including two new cell lines and xenografts driven by CIC::DUX4 and CIC::NUTM1 fusion, respectively. Functional analyses revealed that CIC- rearranged sarcomas are MYC-driven cancers and can be targeted with the selective CDK2 inhibitor tagtociclib (PF-07104091) in vitro and in vivo. Concomitant with RB1- mediated proliferative arrest, tagtociclib inhibited MYC oncogenic programs. Moreover, combination of tagtociclib with the CDK9 inhibitors KB-0742 or AZD4573 was synergistic and enhanced apoptotic cell death in vitro and in vivo. These results demonstrate anti-tumor effects of concurrent inhibition of CDK2 and CDK9 through MYC transcriptional repression and provide a strong rationale for clinical evaluation of CDK2 and CDK9-targeted combination therapies in patients with CIC-rearranged sarcoma.