The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer.

RAF 激酶家族包括促肿瘤有丝分裂原激活蛋白激酶途径的关键激活剂。RAF 蛋白（尤其是 BRAF 和 CRAF）的过度激活会促进多种癌症的肿瘤进展和耐药性。尽管 BRAF 是研究最多的 RAF 蛋白（部分原因是其在黑色素瘤中的突变发生率较高），但 CRAF 在肿瘤发生和耐药性中的作用正变得越来越具有临床意义。在这里，我们总结了导致 CRAF 活性的主要已知调控机制和基因改变，强调了 CRAF 的不同致癌作用，并根据对激酶活性的影响对RAF1 (CRAF) 突变进行分类。此外，我们强调 CRAF 改变可能对耐药性产生的影响，以及精准治疗如何有效针对 CRAF 依赖性肿瘤。在这里，我们讨论临床前和临床发现，这些发现可能会改善癌症中所有类型致癌RAF1改变的治疗方法。