Ras signaling pathway (RAS) (RAS)

The Ras signaling pathway is a central intracellular transduction network that regulates fundamental cellular processes including growth, proliferation, differentiation, and survival [11, 12]. At its core are the Ras small GTPases—primarily KRAS, HRAS, and NRAS—which function as molecular switches by cycling between an active GTP-bound state and an inactive GDP-bound state [7, 18]. This cycle is regulated by guanine nucleotide exchange factors (GEFs) like SOS1 and GTPase-activating proteins (GAPs) like NF1 [12, 18]. Mutations in Ras genes, particularly KRAS, are among the most common drivers in human cancers, including pancreatic, colorectal, and lung carcinomas, leading to constitutive pathway activation [1, 17]. Beyond malignancy, germline mutations in the pathway cause developmental disorders known as RASopathies, such as Noonan syndrome and Neurofibromatosis type 1 [15, 18]. Therapeutic targeting of Ras signaling has historically been challenging, but recent breakthroughs have led to the approval of direct inhibitors for specific mutants like KRAS G12C [6, 10]. Additionally, the pathway is targeted indirectly through inhibitors of upstream activators or downstream effectors such as RAF and MEK kinases [2, 8].

Other names

Ras-MAPK pathwayRas-ERK pathwayRas-PI3K pathwayRas-Raf-MEK-ERK pathwayp21 Ras signaling

Direct inhibition of mutant Ras proteins (e.g., KRAS G12C), inhibition of downstream effector kinases (RAF, MEK, ERK), inhibition of post-translational farnesylation, and inhibition of upstream regulators (SHP2, SOS1).