Ras proteins exist in 2 different states: an inactive GDP-bound state and an active GTP-bound state. Ras becomes activated when a growth factor ligand binds to a receptor tyrosine kinase located on the cell membrane, causing autophosphorylation of the receptor. This triggers binding of adaptor proteins that interact with Ras, promoting GDP removal and GTP binding. Activated Ras then begins a phosphorylation cascade that results in the activation of mitogen-activated protein kinase (MAPK), which enters the nucleus to influence gene transcription.
Ras proteins have intrinsic GTPase activity that allows them to hydrolyze GTP; this mechanism prevents accumulation of active Ras (GTP-bound) in the absence of hormonal signaling. RAS gene mutations can lead to decreased intrinsic GTPase activity; this results in a constitutively activated Ras protein that causes constant and unregulated cell proliferation. RAS mutations are commonly identified in cancerous tumors, specifically colorectal and pancreatic malignancies.
Tumors with KRAS-activating mutations are resistant to anti-EGFR agents as they have a constitutive activation of a downstream signal that is independent of EGFR stimulation or blockade.
