PLK1 Inhibitor Onvansertib Enhances the Efficacy of Alpelisib in PIK3CA -Mutated HR-Positive Breast Cancer Resistant to Palbociclib and Endocrine Therapy: Preclinical Insights.

Simple Summary: Patients with hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer who have PIK3CA mutations and have progressed on first-line therapies are considered for treatment with alpelisib alongside endocrine therapy (ET). Combination therapeutic strategies may extend the clinical benefit of alpelisib. This study investigated the potential of onvansertib, a highly specific inhibitor of polo-like kinase 1 (PLK1), to enhance the efficacy of alpelisib in preclinical models of HR+ breast cancer. Our findings demonstrated that onvansertib synergizes with alpelisib in PIK3CA-mutant HR+ breast cancer cell lines and patient-derived xenografts that are resistant to ET and cyclin-dependent kinase 4/6 inhibitors. The combination inhibited PLK1 and PI3K signaling, induced cell cycle arrest, and triggered apoptotic death in both cell lines and xenograft tumors. Overall, our preclinical data encourage the clinical exploration of this combination for PIK3CA-mutant HR+ metastatic breast cancer patients progressing on standard-of-care therapies. Background: Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is the preferred first-line treatment for hormone receptor-positive (HR+)/HER2- metastatic breast cancer. Although this is beneficial, acquired resistance leads to disease progression, and patients harboring PIK3CA mutations are treated with targeted therapies such as the PI3Kα inhibitor, alpelisib, alongside ET. Drug-associated resistance mechanisms limit the efficacy of alpelisib, highlighting the need for better combination therapies. This study aimed to evaluate the efficacy of combining alpelisib with a highly specific PLK1 inhibitor, onvansertib, in PIK3CA-mutant HR+ breast cancer preclinical models. Methods: We assessed the effect of the alpelisib and onvansertib combination on cell viability, PI3K signaling pathway, cell cycle phase distribution and apoptosis in PI3K-activated HR+ breast cancer cell lines. The antitumor activity of the combination was evaluated in three PIK3CA-mutant HR+ breast cancer patient-derived xenograft (PDX) models, resistant to ET and CDK4/6 inhibitor palbociclib. Pharmacodynamics studies were performed using immunohistochemistry and Simple Western analyses in tumor tissues. Results: The combination synergistically inhibited cell viability, suppressed PI3K signaling, induced G2/M arrest and apoptosis in PI3K-activated cell lines. In the three PDX models, the combination demonstrated superior anti-tumor activity compared to the single agents. Pharmacodynamic studies confirmed the inhibition of both PLK1 and PI3K activity and pronounced apoptosis in the combination-treated tumors. Conclusions: Our findings support that targeting PLK1 and PI3Kα with onvansertib and alpelisib, respectively, may be a promising strategy for patients with PIK3CA-mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation. [ABSTRACT FROM AUTHOR]