Sreekumar Sreeja, Montaudon Elodie, Klein Davis, Gonzalez Migdalia E, Painsec Pierre, Derrien Héloise, Sourd Laura, Smeal Tod, Marangoni Elisabetta, Ridinger Maya
Cardiff Oncology Incorporated, San Diego, CA 92121, USA.
Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 75005 Paris, France.
Cancers (Basel). 2024 Sep 25;16(19):3259. doi: 10.3390/cancers16193259.
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 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 -mutant HR+ breast cancer preclinical models.
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 -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.
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.
Our findings support that targeting PLK1 and PI3Kα with onvansertib and alpelisib, respectively, may be a promising strategy for patients with -mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation.
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+）/人表皮生长因子受体2阴性（HER2-）转移性乳腺癌的首选一线治疗方案。尽管这种治疗有益，但获得性耐药会导致疾病进展，携带PIK3CA突变的患者会接受PI3Kα抑制剂阿培利司等靶向治疗，同时进行内分泌治疗。与药物相关的耐药机制限制了阿培利司的疗效，凸显了开发更好的联合治疗方案的必要性。本研究旨在评估在携带PIK3CA突变的HR+乳腺癌临床前模型中，阿培利司与高度特异性的PLK1抑制剂万赛替尼联合使用的疗效。
我们评估了阿培利司与万赛替尼联合使用对PI3K激活的HR+乳腺癌细胞系的细胞活力、PI3K信号通路、细胞周期阶段分布和凋亡的影响。在三种对内分泌治疗和CDK4/6抑制剂帕博西尼耐药的携带PIK3CA突变的HR+乳腺癌患者来源异种移植（PDX）模型中评估了联合治疗的抗肿瘤活性。使用免疫组织化学和简单蛋白质免疫印迹分析在肿瘤组织中进行药效学研究。
联合治疗协同抑制细胞活力，抑制PI3K信号传导，诱导PI3K激活的细胞系发生G2/M期阻滞和凋亡。在三种PDX模型中，联合治疗显示出比单药治疗更优的抗肿瘤活性。药效学研究证实联合治疗的肿瘤中PLK1和PI3K活性均受到抑制，且凋亡明显。
我们的研究结果支持，分别用万赛替尼和阿培利司靶向PLK1和PI3Kα，对于接受内分泌治疗加CDK4/6i治疗失败的携带PIK3CA突变的HR+乳腺癌患者可能是一种有前景的策略，值得进行临床评估。
