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

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.