Kirsten rat sarcoma virus oncogene homolog G12X mutant messenger RNA (KRAS G12X mRNA) (KRAS G12X mRNA)

KRAS G12X mutant messenger RNAs (mRNAs) are the transcript templates that encode oncogenic KRAS proteins, which are critical drivers in various cancers including pancreatic, colorectal, and lung adenocarcinoma. Mutations at codon 12 (e.g., G12C, G12D, G12V) impair the intrinsic GTPase activity of the KRAS protein, locking it in an "on" state that promotes continuous cell growth and survival signaling. Targeting the mRNA transcript allows for the therapeutic silencing of KRAS expression before the protein is even synthesized, bypassing the structural challenges associated with designing small molecule inhibitors for certain KRAS variants. Therapeutic modalities targeting these mRNAs include antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), which promote the degradation of the target transcript via RNase H or the RNA-induced silencing complex (RISC). Furthermore, mutant KRAS mRNAs are employed in neoantigen-based mRNA vaccines designed to stimulate a T-cell mediated immune response against tumor cells harboring these specific mutations. Clinical development of these agents often focuses on overcoming delivery barriers to ensure the RNA payload reaches the cytoplasm of tumor cells effectively. A significant challenge in this field is achieving high specificity for the mutant allele to avoid the toxicities associated with inhibiting wild-type KRAS mRNA, which is necessary for normal physiology.

Other names

KRAS codon 12 mutant mRNAKRAS G12C/D/V/R/S/A mRNAMutant KRAS transcriptsKRAS oncogenic mRNA

RNA interference (RNAi), Antisense-mediated mRNA degradation (RNase H), Translation inhibition, or Vaccine-induced immune activation [PubMed: 28619754, NCT03948191]