Protein-RNA interaction dynamics downstream of KRAS activation reveals key regulators of oncogenic KRAS driven cancers.

Oncogenic KRAS mutations rewires cellular signaling, leading to significant alterations in gene expression. RNA-binding proteins (RBPs) play a pivotal role in gene expression regulation by post-transcriptionally controlling various aspects of RNA metabolism. It becomes clear that interactions between RBPs and RNA are frequently dysregulated in numerous cancers. However, how the oncogenic KRAS mutations reshape the post-transcriptional regulatory network mediated by RBPs remain poorly understood. In this study, we have systematically dissected oncogenic KRAS driven alternation of RNA-RBP networks. We identified several cancer-associated RBPs with either increased or decreased RNA binding upon oncogenic KRAS, including PDCD11, which is essential for the viability of KRAS mutant cancers, and ELAVL2, which regulates SNAIL and affects cell migration in KRAS mutant lung cancers. Our study serves as a crucial resource for elucidating RBP regulatory networks in KRAS mutant cancers and may provide new avenues for therapeutic strategies targeting KRAS mutant malignancies.