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 harboringPIK3CAmutations 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, inPIK3CA-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 threePIK3CA-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 withPIK3CA-mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation.
背景：内分泌治疗（ET）联合细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）是激素受体阳性（HR+）/HER2-转移性乳腺癌的首选一线治疗方案。尽管该方案具有临床获益，但获得性耐药会导致疾病进展，携带PIK3CA突变的患者需接受靶向治疗，如PI3Kα抑制剂阿培利司联合ET。药物相关耐药机制限制了阿培利司的疗效，凸显了开发更优联合疗法的必要性。本研究旨在评估阿培利司与高选择性PLK1抑制剂昂瓦塞替联合治疗在PIK3CA突变HR+乳腺癌临床前模型中的疗效。 方法：我们在PI3K通路激活的HR+乳腺癌细胞系中，评估了阿培利司与昂瓦塞替联合用药对细胞活力、PI3K信号通路、细胞周期分布及凋亡的影响。在三种对ET和CDK4/6抑制剂帕博西尼耐药的PIK3CA突变HR+乳腺癌患者来源异种移植（PDX）模型中，评估了联合疗法的抗肿瘤活性。通过免疫组织化学和Simple Western分析对肿瘤组织进行药效学研究。 结果：联合用药在PI3K通路激活的细胞系中能协同抑制细胞活力、阻断PI3K信号传导、诱导G2/M期阻滞并促进细胞凋亡。在三种PDX模型中，联合疗法显示出优于单药治疗的抗肿瘤活性。药效学研究证实联合治疗可同时抑制PLK1与PI3K活性，并在肿瘤组织中引发显著凋亡。 结论：本研究结果表明，对于ET+CDK4/6i治疗失败的PIK3CA突变HR+乳腺癌患者，分别通过昂瓦塞替和阿培利司靶向PLK1与PI3Kα可能是一种具有前景的治疗策略，值得进行临床评估。
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