Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Genes (Basel). 2021 Apr 10;12(4):553. doi: 10.3390/genes12040553.
Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration.
致癌性 RAS（大鼠肉瘤）突变驱动了超过一半的人类癌症，而 RAS 抑制是肿瘤学的圣杯。三十年来，不懈的努力和残酷的失望让我们了解了致癌性 RAS 信号的复杂性，使我们现在能够对这种难以捉摸的蛋白质进行药理学控制。抑制效应途径，如 RAF-MEK-ERK 途径，在很大程度上被证明是令人失望的。到目前为止，这些努力大多旨在阻断 ERK 的激活。在这里，我们讨论了依赖 RAF 的途径，这些途径通过 RAF 的功能调节，而不依赖于催化活性，以及它们作为阻断致癌性 RAS 信号的靶点的潜在作用。我们专注于 RAF 激酶非依赖性功能在细胞凋亡、细胞周期进程和细胞迁移中的作用，这些作用现在已经得到了很好的证明。
