PLK1 inhibition by onvansertib enhances paclitaxel efficacy and overcomes resistance in HR+/HER2- breast cancer refractory to endocrine therapy and CDK4/6 inhibitors

Abstract Hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer that progresses on CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) faces a major therapeutic challenge, and chemotherapy is frequently used despite its modest clinical benefit. Paclitaxel is commonly used in this setting; however, intrinsic and acquired resistance substantially limit the depth and durability of response. Polo-like kinase 1 (PLK1) is a key mitotic regulator implicated in resistance to taxanes and ET/CDK4/6i. We evaluated whether PLK1 inhibition with onvansertib enhances paclitaxel activity in HR+ breast cancer models with intrinsic or acquired ET/CDK4/6i resistance, testing across six cell lines and eight patient-derived xenograft models, including paclitaxel-resistant tumors. The combination synergistically inhibited cell viability in vitro and improved antitumor efficacy in xenograft models. Notably, the combination induced tumor regression across all paclitaxel-resistant models, with complete responses in more than half of treated animals in three of five models, and deep, durable regressions in paclitaxel-sensitive models, markedly outperforming either agent alone. Mechanistically, the combination exacerbated mitotic stress, disrupted spindle architecture, suppressed proliferative and cell-cycle-associated transcriptional programs, and promoted proteasome-dependent c-MYC degradation, resulting in enhanced apoptotic cell death in vitro and in vivo. Importantly, genetic modulation of c-MYC expression altered the apoptotic response, establishing c-MYC downregulation as a key mediator of the observed antitumor efficacy. Collectively, these findings support PLK1 inhibition as a mechanistically rational strategy to potentiate taxane efficacy and overcome resistance in advanced HR+/HER2-negative breast cancer.