KRAS, MYC, and ARF6: inseparable relationships cooperatively promote cancer malignancy and immune evasion.

Mutations in the KRAS gene and overexpression of protein products of the MYC and ARF6 genes occur frequently in cancer. Here, the inseparable relationships and cooperation of the protein products of these three genes in cancer malignancy and immune evasion are discussed. mRNAs encoded by these genes share the common feature of a G-quadruplex structure, which directs them to be robustly expressed when cellular energy production is increased. These three proteins are also functionally inseparable from each other, as follows.　1) KRAS induces MYC gene expression, and may also promote eIF4A-dependent MYC and ARF6 mRNA translation, 2) MYC induces the expression of genes involved in mitochondrial biogenesis and oxidative phosphorylation, and 3) ARF6 protects mitochondria from oxidative injury. ARF6 may moreover promote cancer invasion and metastasis, and also acidosis and immune checkpoint. Therefore, the inseparable relationships and cooperation of KRAS, MYC, and ARF6 appear to result in the activation of mitochondria and the driving of ARF6-based malignancy and immune evasion. Such adverse associations are frequent in pancreatic cancer, and appear to be further enhanced by TP53 mutations. Video Abstract.