Fig. 3

Molecular mechanisms of oncogenic KRAS and MYC cooperation. Active KRAS initiates the phosphorylation of Serine 62 (S62) in the MYC protein via the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphoinositide 3-kinase (PI3K) pathways. KRAS can also regulate MYC through ERK5 and eukaryotic translation initiation factor 4E (eIF4E). Subsequently, the peptidylprolyl-isomerase 1 (PIN1) enzyme facilitates the cis-trans isomerization of Proline 63 (P63). Following this, glycogen synthase kinase-3 (GSK3) phosphorylates Threonine 58 (T58), followed by another round of cis-trans isomerization of P63. Dephosphorylation of S62 is orchestrated by protein phosphatase 2A (PP2A), ultimately marking MYC for ubiquitination. Both GSK3 and PP2A function are inhibited by active KRAS, promoting MYC stabilization. Beyond this principal pathway, various molecules contribute to MYC/RAS cooperation, triggering numerous hallmarks of cancer. Cyclin D2 experiences upregulation in the presence of oncogenic KRAS and MYC, inhibiting p27. PI3K indirectly inhibits p27 by upregulating protein kinase B (AKT) and inhibiting Forkhead box O (FoxO) proteins, thereby facilitating the evasion of growth suppression and replicative immortality. Moreover, the combined action of PI3K with ERK and MYC induces cell death escape. In addition, tumors expressing oncogenic KRAS and MYC release chemokine (C-C motif) ligand 9 (CCL9), activating M2 macrophages to secrete vascular endothelial growth factor (VEGF) and ultimately promoting angiogenesis. In parallel, biomolecules such as glucose, cholesterol, and lipids depend on MYC-induced enzymes like glutamine synthetase (GS), lipoxygenase (LOX), and cyclooxygenase (COX), resulting in metabolic alterations. Moreover, MYC regulates several genes and enzymes responsible of mitochondrial biogenesis and metabolism, such as RNA polymerase mitochondrial (POLMRT), DNA polymerases (POLG), nuclear respiratory factor (NRF-1) and host cell factor 1 (HCF1). In addition, KRAS and MYC interaction activates ADP-ribosylation factor 6 (ARF6), conferring oxidative protection. Finally, oncogenic KRAS and MYC elevate the levels of long non-coding RNA HIF1A-As2, transcription factors zinc finger E-box binding homeobox 1 (ZEB1) and zinc finger protein GLI1, contributing to invasion and migration. Created with BioRender.com