Fig. 4

An overview of the various RAS signal transduction pathways and therapeutic approaches for RAS-mutant tumors. Activation of RTKs promotes the exchange of GDP for GTP in RAS, thereby activating RAS. GTP-bound RAS binds to and activates the effector RAF, which initiates the MAPK signaling cascades. Targeting RTKs can reduce the activation of RAS populations. Inhibition of SOS or SHP2 decreases the GDP–GTP exchange rate, leading to a reduction in the GTP-bound RAS population. Another effector, p110, activates the PI3K signaling cascades. Both the MAPK and PI3K signaling cascades can be inhibited at each kinase tier. ERK: Extracellular signal-regulated kinase; FAK: Focal adhesion kinase; GEFs: Guanine nucleotide exchange factors; MEK: Mitogen-activated protein kinase kinase; PDK1: 3-Phosphoinositide Dependent Protein Kinase-1; PI3K: Phosphatidylinositol 3-kinase; RAF: Rapidly accelerated fibrosarcoma; RalGDS: Ral guanine nucleotide dissociation stimulator; RAS: Rat sarcoma virus; RTK: Receptor tyrosine kinase; SH3: SRC homology 3 domain; SOS: Son of sevenless