The KRAS gene encodes a protein that acts as a central control point for cell growth and division, making it one of the most frequently mutated oncogenes found across various human cancers. Activating mutations in the KRAS protein drive continuous, unregulated cell proliferation, leading to tumor formation. The KRAS G12D alteration is a particularly common and aggressive form of this mutation. It poses a significant challenge in oncology due to its high prevalence in certain tumor types and historical resistance to targeted therapies.
Normal Function of the KRAS Protein
The KRAS protein functions as a molecular switch, receiving signals from outside the cell and relaying them inward to control cellular processes like growth, proliferation, and survival. It cycles between two primary states: an inactive state where it is bound to a guanosine diphosphate (GDP) molecule, and an active state where it is bound to a guanosine triphosphate (GTP) molecule. When growth factors bind to receptors on the cell surface, they initiate a cascade that leads to the activation of KRAS by replacing GDP with GTP, effectively flipping the switch to the “on” position.
In its active, GTP-bound form, KRAS interacts with and activates multiple downstream signaling pathways, notably the Mitogen-Activated Protein Kinase (MAPK) pathway. The MAPK pathway then transmits the growth signal all the way to the cell nucleus, stimulating the transcription of genes that promote cell division. To terminate this signal, the KRAS protein possesses an intrinsic enzymatic activity, called GTPase activity, which hydrolyzes the bound GTP back into GDP. This hydrolysis is often greatly accelerated by GTPase-Activating Proteins (GAPs), returning the KRAS switch to the inactive, “off” state, thereby ensuring cell growth is tightly controlled.
The Specificity of the G12D Alteration
The G12D alteration refers to a specific genetic change where the amino acid Glycine (G) at the 12th position of the KRAS protein is replaced by Aspartate (D). This substitution is a single point mutation that dramatically alters the protein’s function, transforming it from a tightly regulated switch into an oncogenic driver. The Glycine residue at position 12 is located within the P-loop, a region essential for the protein’s ability to hydrolyze GTP.
The introduction of Aspartate, a bulkier and negatively charged amino acid, creates a steric hindrance within the active site. This obstruction severely impairs the intrinsic GTPase activity of KRAS and its ability to interact with GAPs. Consequently, the mutant KRAS G12D protein cannot effectively convert GTP back to GDP, leaving it permanently locked in the active, “on” state. This results in a continuous, unregulated stream of signals through pathways like MAPK and PI3K/AKT, constantly driving the cell to proliferate and evade normal cell death signals.
Cancers Associated with KRAS G12D
The G12D mutation is highly concentrated in certain types of cancer. It is the single most common KRAS mutation found in human tumors, and its presence is associated with an aggressive disease course and a poorer prognosis. Pancreatic ductal adenocarcinoma (PDAC) is the tumor type where this mutation is overwhelmingly dominant, accounting for approximately 35% to 40% of all KRAS mutations in this highly lethal cancer.
The G12D mutation is also highly prevalent in colorectal cancer (CRC), where it represents a significant fraction of all KRAS-mutated cases. In non-small cell lung cancer (NSCLC), the prevalence of KRAS G12D is lower, typically around 2% of total cases, but it remains a clinically relevant subset. Tumors harboring the G12D mutation often exhibit unique genomic characteristics, such as being mutually exclusive with other major oncogenic drivers like BRAF in PDAC, or co-occurring with PIK3CA mutations in CRC.
Developing Targeted Treatment Strategies
For decades, KRAS was considered “undruggable” because its smooth, globular structure lacked the deep binding pockets necessary for small-molecule drugs to attach and inhibit its function. The breakthrough in targeting the related KRAS G12C mutation using covalent inhibitors did not directly translate to G12D. This is because the Aspartate residue at position 12 does not possess the necessary chemical group for covalent binding, necessitating the development of entirely new therapeutic approaches.
A major focus has shifted to developing highly selective, non-covalent inhibitors that can bind to a cryptic pocket on the protein, often referred to as the Switch II pocket. One prominent example is the drug MRTX1133, a potent, non-covalent inhibitor designed to selectively bind to the KRAS G12D protein and lock it in the inactive, GDP-bound state. This agent, along with others, is currently undergoing preclinical and clinical investigation.
Immunotherapies
Beyond direct inhibition, researchers are also exploring strategies such as adoptive T-cell transfer therapies. These therapies involve engineering a patient’s own immune cells to specifically recognize and destroy tumor cells that express the KRAS G12D mutant protein.