Exploring CDK4/6-Dependencies in ex vivo Ovarian Cancer Models

Ovarian cancer (OC) is a clinically and molecularly heterogeneous disease with limited treatment options for the majority of patients, particularly those with homologous-recombination-proficient high-grade serous ovarian cancer (HGSOC) and rarer subtypes such as low-grade serous ovarian cancer. Deregulation of the G1/S cell cycle network is common across all subtypes, suggesting subtype-agnostic vulnerabilities. Here, we assessed CDK4/6 dependency using the selective inhibitor palbociclib across 20 patient-derived ex vivo OC models. A subset of models, including four HGSOC and six rarer subtypes, exhibited marked sensitivity to palbociclib, characterised by low CDKN2A/CDKN2B expression, Rb hypophosphorylation, and G1 cell cycle arrest. In contrast, resistant models showed high CDKN2A expression and reduced or absent RB1. Notably, ABCB1 overexpression--a known resistance mechanism in OC--did not mediate palbociclib resistance. Analysis of longitudinal models revealed diminished CDK4/6 dependency following treatment, accompanied by increased CDKN2A expression. These findings support a model of G1/S control in which tumours diverge into CDK4/6- or CDK2-driven proliferation states, with CDKN2A as a potential biomarker to guide patient selection. The predominance of CDK4/6-inhibitor-resistant HGSOC highlights a priority population for CDK2-targeted therapies, offering new treatment strategies for patients with otherwise limited options.