Alternative splicing of KRAS exon 4 promotes tumor progression via enhanced KRAS4A oncogenic activity

KRAS is a well-established oncogene that exhibits high-frequency mutations at cancer-driver hotspot loci across human cancers. While the oncogenic roles of mutant KRAS have been extensively investigated, the functional significance of KRAS splicing isoforms generated by exon 4 (E4) alternative splicing remains poorly understood. Here, we analyzed the expression patterns of <i>KRAS</i> E4 splicing variants in cancer tissues using The Cancer Genome Atlas (TCGA) data and found that certain cancer types exhibit relatively higher expression of the E4-included <i>KRAS</i> (<i>KRAS4A</i>) splicing variant compared to the E4-excluded KRAS (<i>KRAS4B</i>) splicing variant. Functional analysis revealed that the oncogenic properties of KRAS4A were significantly enhanced compared to those of KRAS4B. Furthermore, we identified RBM47 and PTBP1 as key regulators that promote <i>KRAS</i> E4 inclusion. Our findings demonstrate that RBM47- and PTBP1-mediated alternative splicing of <i>KRAS</i> contributes to enhanced tumor progression, highlighting <i>KRAS</i> alternative splicing as a promising therapeutic target for cancer treatment.