The role of Ephexin1 in translation and mTOR-targeted cancer therapy

Ephexin1, also known as neuronal guanine nucleotide exchange factor (NGEF), plays a key role in axon guidance and synaptic homeostasis. However, our recent studies have revealed a critical role for Ephexin1 in the pathogenesis of colon and lung cancers. Here we used multidisciplinary approaches to further explore the underlying mechanisms of Ephexin1 in cancer progression. We discovered that Ephexin1 is essential for promoting polysome formation by coordinating the assembly of translation initiation complexes. Our investigations into gene expression affected by Ephexin1 deficiency showed that Ephexin1 specifically promotes the translation of genes containing 5'-terminal oligopyrimidine (TOP) or 5'-TOP-like motifs, identifying Ephexin1 as a key mediator of mTOR-regulated translation. Importantly, we found that the efficacy of mTOR inhibitors in treating lung cancer was significantly enhanced in a mouse xenograft model when Ephexin1 was deficient. This suggests that Ephexin1 could serve as a synthetic lethality target for mTORC1-targeting therapeutics in cancer treatment. Our findings provide mechanistic insights into the role of Ephexin1 in cancer pathogenesis and highlight its potential as a therapeutic target for improving current cancer treatment strategies.