Kirsten rat sarcoma virus proto-oncogene (KRAS) G12D mutant neoantigen (KRAS G12D neoantigen)

The Kirsten rat sarcoma virus proto-oncogene (KRAS) G12D mutant neoantigen is a tumor-specific epitope resulting from a point mutation where glycine at position 12 is replaced by aspartic acid [1.2.3, 1.4.1]. This mutation is a primary oncogenic driver in several aggressive malignancies, including pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer [1.3.1, 1.3.2]. As a neoantigen, the mutated peptide is processed by the proteasome and presented on the cell surface by specific Human Leukocyte Antigen (HLA) molecules, such as HLA-A*11:01 or HLA-C*08:02, making it a highly specific target for the adaptive immune system [1.2.1, 1.2.2]. Therapeutic strategies targeting this neoantigen include adoptive T-cell therapies (TCR-T), cancer vaccines like ELI-002, and T-cell engaging bispecifics such as IMC-KRASG12D, which aim to elicit a cytotoxic immune response against tumor cells [1.2.4, 1.2.5, 1.4.1]. Additionally, small molecule inhibitors like MRTX1133 and degraders like setidegrasib (ASP3082) specifically target the KRAS G12D protein to disrupt constitutive signaling [1.3.1, 1.3.2, 1.3.4]. The specificity of the neoantigen allows for precision medicine approaches, though efficacy is often restricted by the patient's specific HLA genotype [1.2.2, 1.4.2]. Despite its promise, challenges such as the immunosuppressive tumor microenvironment and the potential for immune evasion through HLA loss remain significant hurdles in clinical application [1.1.1, 1.2.1]. Recent clinical successes, including regression of metastatic lesions in patients treated with KRAS G12D-specific T cells, have validated this neoantigen as a potent therapeutic target [1.2.1, 1.2.4].

Other names

KRAS G12DKRAS p.G12Dmutant KRAS G12D peptideKRAS G12D epitope

Inhibition of GTPase activity, T-cell mediated cytotoxicity, and targeted protein degradation [1.2.4, 1.3.1, 1.3.2].