Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Dis Model Mech. 2022 Feb 1;15(2). doi: 10.1242/dmm.049107. Epub 2022 Feb 18.
The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.
RAS 病是一组由 RAS/MAPK 通路组成部分的基因种系突变引起的疾病。这些疾病包括神经纤维瘤病 1 型、努南综合征、心面肩发育不良综合征、Costello 综合征和 Legius 综合征等，由于 RAS/MAPK 功能障碍，它们具有重叠的临床特征。虽然几种 RAS 病非常罕见，但总的来说，这些疾病相对常见。在这篇综述中，我们讨论了与 RAS 病相关的遗传变异的发病机制，以及通过研究 RAS 病获得的关于 RAS/MAPK 信号的知识。我们还描述了 RAS 病的细胞和动物模型，并探讨了新兴的 RAS 病基因。还讨论了针对 RAS 病的靶向药物作为治疗方法的临床前和临床经验，最后，我们综述了最近开发的针对 RAS/MAPK 驱动的恶性肿瘤的药物（如 RAS 激活抑制剂、直接 RAS 抑制剂和 RAS/MAPK 通路抑制剂）如何用于 RAS 病患者。
