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

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. 18 ovarian cancer cell lines dosed with BLU-222, a CDK2 inhibitor, at cell line IC-50 or DMSO (3 replicates each). Collected 24hr post dose.

为进一步明晰在CCNE1、Rb及p16表达背景下细胞对BLU-222的应答特征，我们分析了BLU-222诱导的18株卵巢癌细胞系的基因表达变化。该细胞系面板包含应答者（生长抑制50%浓度（Growth Inhibition 50%, GI50） ≤200 nM）与非应答者（GI50 >200 nM），涵盖CCNE1扩增、CCNE1拷贝数（Copy Number, CN）升高及CCNE1正常的细胞系。
针对每株细胞系，我们以其增殖性GI50浓度的BLU-222进行处理，并分别对BLU-222处理组与二甲基亚砜（Dimethyl sulfoxide, DMSO）处理组的细胞开展差异信使RNA（messenger RNA, mRNA）表达分析，以计算mRNA表达倍数变化并筛选显著差异表达基因。
18株卵巢癌细胞系分别以BLU-222（一种细胞周期蛋白依赖性激酶2（Cyclin-dependent kinase 2, CDK2）抑制剂）的细胞系半最大抑制浓度（Half-maximal inhibitory concentration, IC50）或DMSO处理，每组设置3次生物学重复，于给药后24小时收集样本。