Michael S. Lawrence

RB-independent activity of CDK2 inhibition in CDK4/6 inhibitor-resistant models

Quantitative imaging analysis of tumor biopsies

CDK2 inhibition does not activate RB

Phosphoproteomic analysis after CDK2 inhibitor treatment

On-target and p53-dependent activity of CDK2 inhibition

Efficacy of CDK2 inhibition in patient-derived CDK4/6 inhibitor-resistant cell lines

Gene amplification profile of the MGH321.4 model

Genomic alterations in models with acquired resistance to CDK4/6i

Expression of cell cycle genes in paired CDK4/6i-sensitive and -resistant models

Intrinsic and acquired resistance to CDK4/6 inhibitors (CDK4/6i) is a critical challenge in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). CDK2 inhibitors (CDK2i) show promise in this context, with several currently under early-phase clinical evaluation. Here, by analyzing tumor and liquid biopsies from patients treated with the selective CDK2i PF-07104091, we observed that PF-07104091 monotherapy achieved disease stabilization in a cohort of CDK4/6i-resistant HR+/HER2- MBC patients. Notably, responses were observed irrespective of RB expression and phosphorylation, whereas non-progressive disease appeared more frequently among patients whose tumors retained wild-type TP53. Studies in established and patient-derived cell lines further substantiated that the growth suppressive effects of CDK2i were independent of RB status in CDK4/6i-resistant models. CDK2i activity reduced DNA replication rate, increased DNA damage, and inhibited mitotic entry, with growth inhibition dependent on p53 expression. These findings indicate that CDK dependency shifts from CDK4/6 toward CDK2 as cells transition from CDK4/6i-sensitive to CDK4/6i-resistant state. The distinct mechanisms of CDK2i and CDK4/6i support enhanced synergistic activity in HR+/HER2- MBC with acquired resistance to CDK4/6i therapy.