Abstract

A broad range of aggressive cancers harbor cyclin E1 (CCNE1) gene amplifications. CCNE1 amplification has been associated with poor survival in ovarian cancer, representing an unmet medical need. Cyclin E1 is the canonical binding partner of cyclin-dependent kinase 2 (CDK2) and the cyclin E1-CDK2 complex drives G1/S progression of the cell cycle. CDKs are a class of enzymes that, along with their regulatory cyclin binding partners, drive cell cycle progression. Cell lines harboring CCNE1 amplification are sensitive to CDK2 knockout or catalytic inhibition with ATP-competitive molecules, suggesting CDK2 may be an attractive therapeutic target for CCNE1-amplified cancers. Selectively inhibiting CDK2 for CCNE1-amplified tumors may limit off-target CDK-driven toxicities. BLU-222 is an orally available, selective investigational CDK2 inhibitor. The poster presents preclinical validation studies leading to the development of BLU-222 for the treatment of patients with ovarian cancer harboring a CCNE1 amplification. CCNE1 copy number increase was a strong predictor of response to CDK2 inhibition across tumor types in cellular systems. BLU-222 is a selective and potent CDK2 inhibitor that arrested cells at the G1/S boundary in an Rb-dependent manner. BLU-222 as monotherapy showed antitumor activity in a CCNE1-amplified CDX tumor model. The combinations of BLU-222 with carboplatin (SOC first-line treatment), BLU-222 with olaparib, and BLU-222 with gemcitabine all induced tumor regression that was sustained even after treatment cessation. Taken together, this evidence provides scientific rationale for the clinical development of BLU-222 as a monotherapy and in combination with SOC agents in CCNE1-amplified cancers.