Kirsten rat sarcoma virus oncogene homolog G12V messenger RNA (KRAS G12V mRNA)

Kirsten rat sarcoma virus oncogene homolog G12V messenger RNA (KRAS G12V mRNA) is the nucleic acid intermediate that encodes a mutant version of the KRAS GTPase, where a glycine at position 12 is substituted by valine (UniProt: P01116). This specific point mutation impairs the intrinsic GTPase activity of the resulting protein and confers resistance to GTPase-activating proteins (GAPs), leading to a constitutively active state that drives persistent signaling through the MAPK/ERK and PI3K/AKT pathways (PubMed: 30475799). KRAS G12V is a critical driver in several aggressive malignancies, most notably appearing in approximately 30% of KRAS-mutant pancreatic cancers and a significant portion of colorectal and lung adenocarcinomas (NIH: National Cancer Institute). Because the KRAS protein has historically been considered undruggable due to its smooth surface and high affinity for GTP, targeting the mRNA transcript has emerged as a viable alternative to prevent the synthesis of the oncogenic protein. Current clinical approaches include mRNA vaccines like mRNA-5671, which utilize the G12V sequence to prime the immune system against tumor cells, and RNA interference technologies designed to silence the gene at the post-transcriptional level (ClinicalTrials.gov: NCT03948191). These mRNA-targeted therapies represent a precision oncology frontier aiming to overcome the limitations of traditional small-molecule inhibitors.

Other names

KRAS G12V transcriptKirsten rat sarcoma 2 viral oncogene homolog G12V mRNAKRAS proto-oncogene, GTPase G12V mRNAc-K-ras G12V mRNA

Therapeutic strategies targeting KRAS G12V mRNA include RNA interference (RNAi) using small interfering RNAs (siRNAs) to induce sequence-specific degradation of the transcript, antisense oligonucleotides (ASOs) that inhibit translation or trigger RNase H-mediated cleavage, and mRNA vaccines that deliver the mutant sequence to dendritic cells to stimulate a neoantigen-specific cytotoxic T-lymphocyte response (PubMed: 31548601, PubMed: 34258437).