Solzak Jeffrey P, Atale Rutuja V, Hancock Bradley A, Sinn Anthony L, Pollok Karen E, Jones David R, Radovich Milan
Department of Surgery, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN USA.
In Vivo Therapeutics Core, Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN USA.
NPJ Breast Cancer. 2017 Apr 26;3:17. doi: 10.1038/s41523-017-0016-8. eCollection 2017.
Triple negative breast cancer accounts for 15-20% of all breast cancer cases, but despite its lower incidence, contributes to a disproportionately higher rate of mortality. As there are currently no Food and Drug Administration-approved targeted agents for triple negative breast cancer, we embarked on a genomic-guided effort to identify novel targeted modalities. Analyses by our group and The Cancer Genome Atlas have identified activation of the PI3K-pathway in the majority of triple negative breast cancers. As single agent therapy is commonly subject to resistance, we investigated the use of combination therapy against compensatory pathways. Herein, we demonstrate that pan-PI3K inhibition in triple negative breast cancers results in marked activation of the Wnt-pathway. Using the combination of two inhibitors currently in clinical trial as single agents, buparlisib(pan-PI3K) and WNT974(WNT-pathway), we demonstrate significant in vitro and in vivo synergy against triple negative breast cancer cell lines and xenografts. Taken together, these observations provide a strong rationale for testing dual targeting of the PI3K and WNT-pathways in clinical trials.
三阴性乳腺癌占所有乳腺癌病例的15%-20%，尽管其发病率较低，但死亡率却高得不成比例。由于目前尚无美国食品药品监督管理局批准的用于三阴性乳腺癌的靶向药物，我们开展了一项基于基因组指导的工作，以确定新的靶向治疗方法。我们团队和癌症基因组图谱的分析已确定，大多数三阴性乳腺癌中存在PI3K通路的激活。由于单药治疗通常会产生耐药性，我们研究了针对补偿通路的联合治疗方法。在此，我们证明三阴性乳腺癌中的泛PI3K抑制会导致Wnt通路的显著激活。使用目前正在进行单药临床试验的两种抑制剂buparlisib（泛PI3K）和WNT974（Wnt通路）联合使用，我们证明了对三阴性乳腺癌细胞系和异种移植瘤具有显著的体外和体内协同作用。综上所述，这些观察结果为在临床试验中测试PI3K和Wnt通路的双重靶向治疗提供了有力的理论依据。
