Ras proto-oncogene protein (mutant forms) (Ras (commonly HRAS, KRAS, NRAS for isoforms))

Mutated Ras protein refers to any oncogenic form of the Ras proto-oncogene family (HRAS, KRAS, NRAS) harboring activating mutations, most commonly at codons 12, 13, or 61. These proteins are small GTPases that regulate critical signaling pathways controlling cell proliferation, survival, and differentiation. Mutations render Ras constitutively active, driving persistent signaling that underpins tumorigenesis, with roles in both cancer and inflammation. Ras mutations are among the most frequent genetic alterations in human cancer, especially in pancreatic, lung, and colorectal tumors, closely linked to poor prognosis and therapeutic resistance. For decades, Ras was thought to be “undruggable” due to its structure, but recent advances have led to the development of mutant-specific inhibitors (e.g. sotorasib, adagrasib for KRAS G12C). Challenges remain, including rapid resistance, modest efficacy, and significant safety concerns. Ras mutational status is both a prognostic and predictive biomarker for several cancers. Other therapeutic strategies target upstream and downstream Ras signaling, or exploit synthetic lethal vulnerabilities specific to cancer cells with mutant Ras.

Other names

Mutant Rasoncogenic RasRas mutantmutated KRAS/NRAS/HRAS

Covalent binding to mutated cysteine (KRAS G12C), locking Ras in inactive GDP-bound state; Inhibition of membrane association via farnesyl transferase inhibitors; Targeting upstream (RTK inhibition) or downstream (MAPK/MEK) signaling blockers; Synthetic lethality approaches targeting Ras-associated vulnerabilities (e.g., Rac1, SHP2)