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-naive 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... (for more see dbGaP study page.)