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

Abstract

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.

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

“…58 At phenotypic level, ARF6 also regulates various cytoskeletal processes which eventually promote cancer cell migration, and cell invasionboth critical processes for metastasis. [13][14][15] Indeed, we also observed that the shRNA-mediated downregulation of ARF6 resulted in stinted proliferation and Matrigel invasion in vitro. Importantly, our study, unlike most previous studies, introduces a temporal dimension.…”

“…58 At phenotypic level, ARF6 also regulates various cytoskeletal processes which eventually promote cancer cell migration, and cell invasion – both critical processes for metastasis. 13–15…”

“…ARF6 is a small GTPase of the Ras family of GTPAses and is a major mediator of KRAS signalling. Loss of ARF6 has been studied to impair proliferation, migration and invasion, [13][14][15][16][17][18][19] which in turn has prompted the development of ARF6 inhibitor NAV-2729, 20 and is considered as a potential therapeutic target. 21 For instance, ARF6 is an inhibitor of the RLS3induced ferroptosis and a promoter of gemcitabine resistance in PDAC.…”

“…15 KRAS-downstream signalling acts on both ARF6 and ASAP1 to downregulate E-cadherin and promote a more mesenchymal phenotype. 13,15 Additionally ASAP1 can also regulate cytoskeletal features such as β1 integrins leading to a PDAC invasive phenotype. 22 In addition to promoting tumour invasiveness, ARF6, through ASAP1 also promotes the intracellular recycling and cell surface expression of programmed death ligand 1 (PD-L1), which binds to the PD-1 receptors on immune cells, leading to immune checkpoint evasion.…”

Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?

“…87,88 Other notable mutations in HCC and CCA are of the MYC oncogene and Kirsten rat sarcoma virus (KRAS) gene, which in turn induces overexpression of the MYC oncogene, leading to increased oncogenesis, suppressed immunity and antigen presentation, and activated TGF-β signaling. [89][90][91][92][93] Likewise, isocitrate dehydrogenase 1 (IDH1) mutations are common in CCA 94 and have been linked to immune evasion in mouse models. 95 Finally, signaling pathways like mammalian target of rapamycin (mTOR), 96 TGFβ, 78 and IFN-γ/JAK/STAT 97,98 are frequently affected by mutations in primary liver cancer, promoting tumor proliferation and potentially adding to ICI resistance.…”