Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.

胰腺导管腺癌 (PDAC) 是由KRAS和TP53的共存突变驱动的。然而，这些突变如何协同促进这种癌症尚不清楚。在这里，我们发现了由增强 KRAS 活性的突变体 p53 强制执行的 RNA 剪接中的序列特异性变化。突变体 p53 增加剪接调节因子 hnRNPK 的表达，以促进富含胞嘧啶的外显子包含在 GTP 酶激活蛋白 (GAP) 中，GAP 是 RAS 家族成员的负调节因子。突变的 p53 强制 GAP 亚型失去细胞膜结合，导致 KRAS 活性增强。防止突变体 KRAS/p53 PDAC 中富含胞嘧啶的外显子包含在内会降低肿瘤生长。此外，突变体 p53 PDAC 通过剪接体抑制剂对剪接抑制敏感。这些数据提供了对 KRAS 和 p53 突变的共同富集以及针对 PDAC 中该机制的疗法的见解。