所有人类癌症中超过30%是由RAS突变所驱动的，激活KRAS突变存在于两种主要的结直肠癌（CRC）亚组中，即MSS（微卫星稳定）和MSI（微卫星不稳定）亚组中，占40%。 RAS驱动的肿瘤研究表明，RAS效应物RAF及特别是RAF1扮演重要角色，且可能依赖或独立于RAF激活MEK / ERK模块的能力。本研究表明，RAF1而不是其激酶活性，在MSI和MSS CRC细胞株衍生的球体和患者衍生的器官中，无论KRAS突变状态如何，都发挥着关键作用。此外，我们可以定义一种RAF1转录组签名，其中包括有助于STAT3激活的基因，并且可证明RAF1消融可减少所有CRC球体中STAT3的磷酸化。参与STAT3激活以及促进血管生成的STAT3靶基因也在表达RAF1水平较低的人类原发性肿瘤中下调。这些结果表明，无论KRAS状态如何，RAF1都可能是MSI和MSS CRC中一个吸引人的治疗靶点，并支持开发选择性RAF1降解剂而非RAF1抑制剂用于联合治疗的临床应用。©2023年。作者（S）。

More than 30% of all human cancers are driven by RAS mutations and activating KRAS mutations are present in 40% of colorectal cancer (CRC) in the two main CRC subgroups, MSS (Microsatellite Stable) and MSI (Microsatellite Instable). Studies in RAS-driven tumors have shown essential roles of the RAS effectors RAF and specifically of RAF1, which can be dependent or independent of RAF's ability to activate the MEK/ERK module. In this study, we demonstrate that RAF1, but not its kinase activity, plays a crucial role in the proliferation of both MSI and MSS CRC cell line-derived spheroids and patient-derived organoids, and independently of KRAS mutation status. Moreover, we could define a RAF1 transcriptomic signature which includes genes that contribute to STAT3 activation, and could demonstrate that RAF1 ablation decreases STAT3 phosphorylation in all CRC spheroids tested. The genes involved in STAT3 activation as well as STAT3 targets promoting angiogenesis were also downregulated in human primary tumors expressing low levels of RAF1. These results indicate that RAF1 could be an attractive therapeutic target in both MSI and MSS CRC regardless of their KRAS status and support the development of selective RAF1 degraders rather than RAF1 inhibitors for clinical use in combination therapies.© 2023. The Author(s).