The three human RAS genes (KRAS, NRAS and HRAS) are the most frequently mutated oncogenes in human cancer appearing in 90% of pancreatic, 35% of lung and in 50% of colon cancers (1,2,3)
RAS proteins are binary switches, cycling between ON and OFF states during signal transduction
- these switches are normally tightly controlled, but in RAS-related diseases, such as cancer mutations in the RAS genes or their regulators render RAS proteins persistently active
- KRAS is the isoform prevalently mutated in pancreas, lung and colon cancer
- mutated KRAS is a major driver for malignant transformation in pancreatic tumors and in lung adenocarcinoma, as mutations are detected in early lesions, retained in all metastases and are a hallmark in the exposure to tobacco smoke, respectively (2)
- in colon cancer, KRAS mutations occur as an early event in about 50% of cases
- NRAS is the predominant isoform mutated in cutaneous melanomas and acute myelogenous leukemia
- HRAS is the predominant isoform mutated in bladder cancer
- reasons for this high prevalence of RAS mutation in cancers and for the preferential mutation in some kind of cancers still remains to be elucidated
The three human RAS genes that encode four small guanosine triphosphatase (GTPases) are KRAS4A, KRAS4B, HRAS and NRAS
- RAS is the component of the mitogen activated protein kinase (MAPK) signaling pathway, which is activated by a ligand binding to a receptor tyrosine kinase (RTK) such as the epidermal growth factor receptor (EGFR)
- RAS exists in the non-active (GDP, guanosine diphosphatase) or active-state (GTP) and the transition between these two states is responsible for signal transduction events occurring from the cell surface receptor to the inside of the cell which is crucial for cell growth and differentiation (1)
- in physiological conditions
- switch is catalysed by two guanine exchange factors known as SOS1/2, that promote the activation of RAS proteins by stimulating GDP for GTP exchange and GTPase-activating proteins (GAPs), which in turn accelerate RAS-mediated GTP hydrolysis
- the GTP-bound form of RAS is the activated state and, together with the insensitivity to cytosolic GAP, represents the biochemical key defect of mutant RAS proteins, which results in persistent accumulation of the active, GTP-bound protein and activation of multiple downstream effectors
Reference:
- Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13:828-851.
- Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457-2467.
- McCormick F. KRAS as a therapeutic target. Clin Cancer Res. 2015;21:1797-1801