Wang Manxue, Ji Ailing, Gao Ruifang, Hu Sike
Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, China.
Oncogene. 2025 Aug 12. doi: 10.1038/s41388-025-03536-4.
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.
ERK1/2信号通路是最常失调的致癌通路之一，可由多种突变引发，包括RAS、BRAF中的突变以及ERBB2（HER2）的扩增。ERK1/2过度激活与TP53突变同时出现的情况在多种癌症类型中很常见，且与显著更差的临床结果相关。然而，ERK1/2信号与突变型p53之间协同作用的直接机制在很大程度上仍未被探索。我们的研究表明，致癌性KRAS激活c-JUN，这促进了与突变型p53的物理相互作用，导致几个促转移转录网络的过度激活。值得注意的是，突变型p53和c-JUN协同上调EGR1，EGR1是肿瘤侵袭和转移的关键驱动因子。EGR1表达升高的联合效应，以及KRAS和突变型p53激活的信号通路，显著增强了癌细胞的促转移特性。这些发现为KRAS和p53突变的共同富集提供了关键见解，并为针对这种相互作用的新型治疗策略铺平了道路。
