Coexistence of P53 and KRAS mutations enhances ERK1/2 signaling by inducing EGR1 expression through mutp53 and c-JUN interaction.

The ERK1/2 signaling pathway, one of the most frequently dysregulated oncogenic pathways, can be initiated by diverse mutations, including those in RAS, BRAF, and amplifications of ERBB2 (HER2). Co-occurrence of ERK1/2 hyperactivation and TP53 mutations is common in multiple cancer types and correlates with significantly poorer clinical outcomes. However, the direct mechanisms underlying the cooperation between ERK1/2 signaling and mutant p53 remain largely unexplored. Our study demonstrates that oncogenic KRAS activates c-JUN, which facilitates physical interactions with mutant p53, leading to hyperactivation of several pro-metastatic transcriptional networks. Notably, mutant p53 and c-JUN collaboratively upregulate EGR1, a key driver of tumor invasion and metastasis. The combined effects of elevated EGR1 expression, along with signaling pathways activated by KRAS and mutant p53, significantly enhance pro-metastatic traits in cancer cells. These findings provide crucial insights into the co-enrichment of KRAS and p53 mutations and pave the way for novel therapeutic strategies targeting this interaction.