GTPase KRAS isoform 4A (KRAS4A)

KRAS4A is a splice variant of the Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the Ras GTPase family that functions as a critical molecular switch in signal transduction (UniProt P01116). It cycles between an active GTP-bound state and an inactive GDP-bound state, mediating pathways such as MAPK/ERK and PI3K/AKT that govern cell growth, differentiation, and survival (PubMed: 30103615). While KRAS4B is often considered the dominant isoform, KRAS4A is highly expressed in specific tissues and plays a unique role in cancer metabolism and stemness (PubMed: 29358046). Mutations in KRAS, most commonly at codon 12, result in impaired GTP hydrolysis and persistent signaling, driving the progression of pancreatic, colorectal, and lung cancers (NIH: National Cancer Institute). Historically considered "undruggable," recent advancements have led to the development of covalent inhibitors like sotorasib and adagrasib that specifically target the KRAS G12C mutation found in both isoforms (PubMed: 31666102). Therapeutic strategies now focus on overcoming adaptive resistance and expanding targeting to other common mutations like G12D and G12V. KRAS4A's distinct membrane localization and post-translational modifications make it a subject of ongoing research for isoform-specific therapeutic intervention.

Other names

Kirsten rat sarcoma virus oncogene homolog isoform 4AKRAS variant Ap21RASK2

Covalent inhibition of the KRAS G12C mutant protein, locking it in the inactive GDP-bound state to prevent downstream signaling.