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Determinants of response to BLU-222, a potent and highly selective CDK2 inhibitor, in CCNE1-aberrant ovarian and endometrial tumors

ABSTRACT: Determinants of response to BLU-222, a potent and highly selective CDK2 inhibitor, in CCNE1-aberrant ovarian and endometrial tumors

PROVIDER: PRJNA1186705 | ENA |

REPOSITORIES: ENA

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Determinants of response to BLU-222, a potent and highly selective CDK2 inhibitor, in CCNE1-aberrant ovarian and endometrial tumors

Project description:To further refine our understanding of BLU-222 response in the context of CCNE1, Rb, and p16 expression, we analyzed BLU-222 induced gene expression changes in 18 ovarian cancer cell lines. This panel of responders (GI50 ≤200 nM) and non-responders (GI50 >200 nM) included CCNE1-amplified, CCNE1 CN-increased, and CCNE1-normal cell lines. Each cell line was treated with BLU-222 at its proliferative GI50 and differential mRNA expression analysis between BLU-222 treated cells and DMSO treated cells was performed for each cell line to calculate mRNA expression fold change and identify significantly differentially expressed genes.

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Differential responses to selective CDK2 inhibitor BLU-222 is conditioned by tumor suppressors

Project description:The selective CDK2 inhibitor BLU-222 was evaluated for mechanisms of response in the context of ovarian and breast cancer models. Using sensors of cellular CDK activity, it was found that sensitivity to either CDK4/6 or CDK2 inhibition is related to the differential dependence on a single CDK for G1/S transition. Unlike CDK4/6 inhibitors, BLU-222 was able to robustly inhibit proliferation through cell cycle inhibition in both G1 and G2 phases. However, it remained possible for cells to re-enter the cell cycle upon drug withdrawal. The anti-proliferative strength and impact on G1/S versus G2/M accumulation was found to be mediated by the RB tumor suppressor, as determined by functional perturbation strategies. To broaden the sensitivity to CDK2 inhibition, combinatorial drug screens were performed that identified both synergistic (e.g., CDK4/6 inhibitors) and antagonistic (e.g., WEE1 inhibitors) relationships. Models that were exceptionally sensitive to CDK2 inhibition displayed coordinate expression of Cyclin E1 and P16INK4A, an endogenous CDK4/6 inhibitor. Functional studies demonstrated that P16INK4A and CDK4/6 activity were key mediators of sensitivity to BLU-222. Clinical gene and protein expression analysis revealed a positive correlation between Cyclin E1 and P16INK4A and that ~25% of ovarian cancers exhibited coordinate expression of Cyclin E, P16INK4A, and RB, indicative of strong sensitivity to CDK2 inhibition. Together, this work advances a precision strategy for the use of CDK2 inhibitors in the context of ovarian and breast cancers.

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Project description:Cyclin E1 (CCNE1) is amplified in various tumor types including high-grade serous ovarian cancer where it is associated with poor clinical outcome. We have demonstrate that suppression of the Cyclin E1 partner kinase, CDK2, induces apoptosis in a CCNE1 amplicon-dependent manner. Little is known of mechanisms of resistance to CDK inhibitors. We therefore generated OVCAR-3 sublines with reduced sensitivity to CDK2 inhibitors and profiled by SNP copy number microarrays. Arrayed samples included parental OVCAR-3 cells and five independently derived sublines resistant to PHA-533533 (OVCAR3-533533-R1, -R3, -R5, -R6, -R7). The resistant cell lines were arrayed after drug selection (P5).

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