CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 ORE, UK.
Nat Commun. 2021 Jan 4;12(1):56. doi: 10.1038/s41467-020-20255-4.
RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2 Vav3 Tiam1), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.
RAC1 活性对于肠道稳态至关重要，并且对于肿瘤抑制基因 Apc 在小鼠肠道中缺失所驱动的过度增殖是必需的。为了避免直接靶向对稳态的影响，我们推断通过 RAC-GEFs 间接靶向 RAC1 可能是有效的。对 Apc 缺陷肠道组织的转录谱分析确定了 Vav3 和 Tiam1 为关键靶标。这些基因的缺失表明，虽然 TIAM1 缺陷可以抑制 Apc 驱动的过度增殖，但对肿瘤发生没有影响，而 VAV3 缺陷没有影响。有趣的是，这两种基因的缺失都导致了 Vav2 的上调，随后靶向所有三种（Vav2 Vav3 Tiam1），强烈抑制过度增殖、肿瘤发生和 RAC1 活性，而不影响正常稳态。至关重要的是，观察到的 RAC-GEF 依赖性被致癌 KRAS 突变所否定。总之，这些数据表明，尽管靶向 RAC-GEF 分子在早期阶段可能具有治疗效果，但在晚期疾病中，这种益处可能会丧失。
