U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.

The mechanisms by which mutations of splicing factor gene U2AF1 contribute to lung adenocarcinoma pathogenesis are not well understood. Here we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the impact on alternative splicing. One specific KRAS mutation, G12S, led to skipping of KRAS exon 2 and generation of a nonfunctional KRAS transcript. However, expression of the U2AF1 mutant reverted this exon skipping and restored KRAS function, leading to enrichment of U2AF1 mutations in KRAS-mutant lung adenocarcinomas. Comprehensive analysis of splicing factor-oncogene mutation co-occurrence in cancer genomes also revealed significant coenrichment of KRAS and U2AF1 mutations. Experimentally, KRAS mutation led to KRAS exon 3 skipping, which in turn could be rescued by expression of U2AF1. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations in a dynamic process of cascading selection.