KRASMAPK

KRASMAPK refers to the signaling axis consisting of KRAS and the downstream mitogen-activated protein kinase (MAPK) cascade that relays signals from receptor tyrosine kinases to the nucleus to regulate cell proliferation, differentiation, and survival. Activation begins when RTKs stimulate guanine nucleotide exchange factors such as SOS, loading KRAS with GTP. Active KRAS-GTP engages RAF kinases (CRAF/RAF1 or BRAF), which phosphorylate and activate MEK1/2, which in turn activate ERK1/2. ERK translocates to the nucleus to modulate gene expression.

In normal cells, this pathway integrates multiple cues to control growth and development. In cancer, mutations in KRAS or aberrant upstream signaling can lead to constitutive MAPK activation. KRAS mutations, particularly in codon 12 (e.g., G12D, G12V, G12C), are common in pancreatic, colorectal, and lung cancers and drive oncogenesis by promoting uncontrolled cell division and survival.

Therapeutically, KRAS has been challenging to target, but selective inhibitors of specific KRAS mutants have emerged (notably KRAS G12C inhibitors such as sotorasib and adagrasib). Other strategies target downstream MEK or RAF kinases, and combination therapies are explored to overcome resistance and feedback activation. The KRAS-MAPK pathway interacts with parallel signaling networks, including PI3K-AKT, and feedback loops can influence treatment response.

Diagnostic testing for KRAS mutations informs prognosis and therapeutic decisions in several cancers and can guide inclusion in targeted therapy trials. Ongoing research aims to broaden mutant-specific inhibitors, overcome resistance, and define effective combinations.