KRAS Pathway (None)

The KRAS pathway refers to the signaling cascade initiated and regulated by the KRAS protein, a small GTPase that acts as a molecular switch in cells. The pathway is central to cell proliferation, differentiation, and survival. Dysregulation of this pathway—most commonly through oncogenic mutations in the KRAS gene—is implicated in many cancers, including lung, colorectal, and pancreatic cancers. The KRAS protein cycles between an inactive GDP-bound state and an active GTP-bound state. Activation occurs when guanine nucleotide exchange factors (GEFs) promote the release of GDP so that GTP can bind; deactivation is accelerated by GTPase-activating proteins (GAPs), which stimulate hydrolysis of GTP back to GDP. In its active (GTP-bound) form, KRAS interacts with multiple downstream effectors—including RAF kinases (MAPK/ERK pathway), PI3K (PI3K/AKT/mTOR pathway), and RalGDS—to propagate signals from receptor tyrosine kinases such as EGFR or PDGFR. Oncogenic mutations often occur at codons 12, 13, or 61—these disrupt intrinsic/extrinsic regulation by GAPs leading to constitutive activation. KRAS is one of the most frequently mutated oncogenes across human cancers. Mutations lock it into its active state regardless of upstream signals, drives uncontrolled cell growth, promotes resistance to apoptosis, and contributes to metabolic reprogramming. Mutant forms are especially prevalent in non-small cell lung cancer (~25%), pancreatic ductal adenocarcinoma (>90%), and colorectal cancer (~40%).

Inhibition of downstream signaling pathways (MEK, PI3K/mTOR); Direct KRAS inhibition; Disruption of membrane localization; Immunotherapies targeting mutant-specific neoantigens