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CDK2 Inhibition Demonstrates RB-Independent Efficacy in CDK4/6 Inhibitor-Resistant HR-Positive/HER2-Negative Breast Cancer

Preliminary clinical data from hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative metastatic breast cancer (MBC) patients with resistance to CDK4/6 inhibitors treated with the CDK2 inhibitor PF-07104091 as monotherapy indicate that therapeutic efficacy correlates with TP53 status, but not with RB expression or phosphorylation. Using a panel of HR+/HER2- MBC patient-derived (PD) cell lines, including both CDK4/6 inhibitor-naïve and resistant models, we found that CDK2, unlike CDK4/6, is dispensable for RB phosphorylation. Notably, in models derived from tumors that had progressed on CDK4/6 inhibitor therapy, as well as in models with acquired in vitro resistance, CDK2 inhibition reduced DNA replication rate, induced DNA damage, and inhibited mitotic entry in an RB-independent manner.

Data available through this dbGaP submission include whole-exome sequencing (WES) from four CDK4/6 inhibitor-naïve HR+/HER2- MBC PD cell lines (MGH10035.1, MGH10035.2, MGH358.1, and MGH358.2), their corresponding isogenic derivatives with acquired in vitro resistance to the CDK4/6 inhibitor palbociclib, and one PD cell line (MGH321.4) derived from a letrozole/ribociclib-resistant HR+/HER2- MBC tumor. MGH10035.1 and MGH10035.2 were derived from the same patient at different stages of treatment, as were MGH358.1 and MGH358.2.