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 KRAS 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 KRAS (KRAS4A) splicing variant compared to the E4-excluded KRAS (KRAS4B) 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 KRAS E4 inclusion. Our findings demonstrate that RBM47- and PTBP1-mediated alternative splicing of KRAS contributes to enhanced tumor progression, highlighting KRAS alternative splicing as a promising therapeutic target for cancer treatment.