Carmona F Javier, Montemurro Filippo, Kannan Srinivasaraghavan, Rossi Valentina, Verma Chandra, Baselga José, Scaltriti Maurizio
Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program (HOPP), NY, USA.
Unit of Investigative Clinical Oncology, Institute for Cancer Research and Treatment, Candiolo, Italy.
Pharmacol Ther. 2016 Feb;158:63-70. doi: 10.1016/j.pharmthera.2015.11.013. Epub 2015 Dec 2.
The PI3K/AKT pathway is the focus of several targeted therapeutic agents for a variety of malignancies. In ERBB2-amplified breast cancer, the hyperactivation of this signaling cascade is associated with resistance to ERBB2-targeted therapy. This can occur through gain-of-function alterations or compensatory mechanisms that enter into play upon pharmacological pressure. The strong rationale in combining anti-ERBB2 agents with PI3K/AKT inhibitors, together with the identification of genomic alterations conferring sensitivity to targeted inhibition, are guiding the design of clinical studies aimed at preventing the emergence of drug resistance and achieving more durable response. In the present review, we describe the involvement of this pathway in breast cancer pathogenesis, with an emphasis on AKT kinases, and provide insight into currently available targeted agents for the treatment of ERBB2-amplified breast cancer. Finally, we provide preliminary data on a novel AKT3 mutation detected in the context of resistance to anti-ERBB2 therapy as an example of genomics-based approaches towards uncovering novel actionable targets in this setting.
PI3K/AKT信号通路是多种针对不同恶性肿瘤的靶向治疗药物的作用靶点。在ERBB2基因扩增的乳腺癌中，该信号级联反应的过度激活与对ERBB2靶向治疗的耐药性相关。这可能通过功能获得性改变或在药物压力下发挥作用的补偿机制而发生。将抗ERBB2药物与PI3K/AKT抑制剂联合使用的有力理论依据，以及对赋予靶向抑制敏感性的基因组改变的识别，正指导着旨在预防耐药性出现并实现更持久反应的临床研究设计。在本综述中，我们描述了该信号通路在乳腺癌发病机制中的作用，重点关注AKT激酶，并深入探讨了目前可用于治疗ERBB2基因扩增乳腺癌的靶向药物。最后，我们提供了在抗ERBB2治疗耐药背景下检测到的一种新型AKT3突变的初步数据，作为在这种情况下基于基因组学方法发现新的可操作靶点的一个例子。
