PDF(Pubmed)
Abstract：
The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer\'s mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.
摘要：
PI3K/AKT/mTOR信号通路是乳腺癌中最频繁激活的通路之一,并且在几种生理功能的调节中也起着核心作用。通过开发针对三种激酶的抑制剂（PI3K，AKT,和mTOR)。虽然已经开发了多种化合物，目前,只有三种抑制剂被批准在晚期ER阳性患者中靶向该途径，HER2阴性乳腺癌：依维莫司（mTOR抑制剂），alpelisib（PIK3CA抑制剂），和capivasertib（AKT抑制剂）。像大多数靶向抗癌药物一样，耐药性在临床上是一个主要问题,也是经常限制这些药物整体疗效的一个因素.耐药性可以根据其发展的时间范围分为内在或获得性耐药性。尽管内在抗性在特定治疗之前存在，获得性抵抗是由治疗引起的。大多数ER阳性的患者，HER2阴性晚期乳腺癌可能会在其癌症旅程的某个时候提供PI3K/AKT/mTOR通路的抑制剂。可用的选项取决于批准标准和癌症的突变状态。在这一大群患者中，大多数人可能会在某个时候产生抗药性，这使得这是一个感兴趣的领域，目前尚未满足的需求。在这里，我们回顾了针对PI3K/AKT/mTOR信号通路的药物耐药的常见机制，阐述当前的管理方法，并讨论正在进行的临床试验，试图减轻这一重大问题。我们特别强调需要对AKT1抑制剂耐药性进行更多研究。
