Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Urology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Nat Rev Urol. 2020 May;17(5):292-307. doi: 10.1038/s41585-020-0298-8. Epub 2020 Mar 16.
Over the past 5 years, the advent of combination therapeutic strategies has substantially reshaped the clinical management of patients with advanced prostate cancer. However, most of these combination regimens were developed empirically and, despite offering survival benefits, are not enough to halt disease progression. Thus, the development of effective therapeutic strategies that target the mechanisms involved in the acquisition of drug resistance and improve clinical trial design are an unmet clinical need. In this context, we hypothesize that the tumour engineers a dynamic response through the process of cellular rewiring, in which it adapts to the therapy used and develops mechanisms of drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K-AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties. These dynamic responses are specific for each patient and could be responsible for treatment failure despite multi-target approaches. Understanding the common stages of these cellular rewiring mechanisms to gain a new perspective on the molecular underpinnings of drug resistance might help formulate novel combination therapeutic regimens.
在过去的 5 年中，联合治疗策略的出现极大地改变了晚期前列腺癌患者的临床治疗模式。然而，这些联合治疗方案大多是经验性开发的，尽管它们提供了生存获益，但还不足以阻止疾病进展。因此，开发针对耐药性获得机制的有效治疗策略并改进临床试验设计是一个未满足的临床需求。在这种情况下，我们假设肿瘤通过细胞重排过程来设计动态反应，通过关键调节级联（如雄激素受体、PI3K-AKT 或 GATA2 依赖性途径）的下游信号来适应所使用的治疗方法，并发展耐药机制，以及启动生物过程，通过表型转换向神经内分泌表型或获得干性样特性，使肿瘤细胞回复到未分化的侵袭状态。这些动态反应是每个患者特有的，可能导致尽管采用多靶点方法治疗仍失败。了解这些细胞重排机制的共同阶段，可能有助于我们从耐药性的分子基础方面获得新的视角，并制定新的联合治疗方案。
