Genes contain instructions for building and maintaining an organism’s cells, dictating how they grow, divide, and perform specialized functions. The KRAS gene plays a significant role in cell growth and division signaling. A gene mutation is a change in the DNA sequence that can alter these instructions, potentially leading to abnormal protein function. The G12D mutation refers to a change at position 12 in the KRAS protein, where glycine (G) is replaced by aspartate (D). This alteration is a prevalent mutation within the KRAS gene.
The Role of KRAS G12D in Cancer
Normally, the KRAS protein functions like a molecular “on/off switch” that regulates cell growth and division. It cycles between an active state, where it binds to a molecule called GTP, and an inactive state, where it converts GTP to GDP. This precise control ensures that cells only grow and divide when necessary, maintaining balance within tissues.
The G12D mutation, however, “jams” this switch in the “on” position, leading to continuous and unregulated cell signaling. This persistent activation drives uncontrolled cell proliferation. The mutated KRAS protein also contributes to resistance to normal cell death and increases the potential for metastasis.
The KRAS G12D mutation is frequently found in several aggressive cancer types. It is common in pancreatic ductal adenocarcinoma (PDAC), present in approximately 33-40% of cases. This mutation is also observed in about 13-25% of colorectal cancer cases. In non-small cell lung cancer (NSCLC), KRAS G12D is found in about 2-16% of cases, though less common than other KRAS mutations like G12C.
Detecting KRAS G12D
Identifying the KRAS G12D mutation in patients is an important step in modern cancer diagnosis and treatment planning. Molecular testing helps determine if a patient’s tumor harbors specific genetic alterations, which can then guide therapeutic decisions. The primary methods for detecting KRAS G12D involve analyzing genetic material from tumor samples.
One common approach is tissue biopsy, where a small tumor sample is obtained. This tissue is processed to extract DNA, which is then subjected to various molecular tests. Next-Generation Sequencing (NGS) is a comprehensive technology widely used for identifying genetic mutations, including KRAS G12D, by rapidly sequencing large portions of DNA.
Another method is liquid biopsy, a less invasive blood test. This test detects circulating tumor DNA (ctDNA), fragments of DNA released by tumor cells into the bloodstream. Detecting the KRAS G12D mutation in ctDNA provides valuable information for diagnosis, monitoring, and guiding treatment without a tissue biopsy.
Therapeutic Strategies for KRAS G12D
Historically, KRAS mutations were challenging targets for drug development, often labeled “undruggable” due to the protein’s smooth surface. Breakthroughs have occurred, particularly with inhibitors for the KRAS G12C mutation. G12D is a different mutation from G12C, presenting unique challenges and requiring distinct therapeutic approaches.
Direct KRAS G12D inhibitors are being developed to specifically bind to and inhibit the mutated protein, preventing its continuous activation. Several compounds are currently under investigation:
MRTX1133: A non-covalent inhibitor binding to the switch II pocket of KRAS G12D. It shows promising preclinical activity in models of pancreatic, lung, and colorectal cancers and is in Phase 1 clinical trials.
Zoldonrasib: A selective inhibitor targeting RAS G12D. It has shown tumor regressions in preclinical models and is being evaluated in Phase 1 studies for advanced solid tumors.
VS-7375: An investigational oral KRAS G12D inhibitor. It received fast track designation for pancreatic ductal adenocarcinoma, targeting both the active and inactive states of the protein.
Beyond direct inhibitors, strategies that target other proteins in the signaling pathways activated by KRAS G12D are also being explored. These include upstream and downstream pathway inhibitors, such as MEK inhibitors and ERK inhibitors, which aim to block the signals that promote uncontrolled cell growth. Combination therapies, involving the use of multiple drugs, are also being investigated to achieve more comprehensive and durable responses. This approach can help overcome potential resistance mechanisms that might arise with single-agent treatments.
Immunotherapy, which harnesses the body’s immune system to fight cancer, is also being explored in KRAS G12D-driven cancers. Research is ongoing into synergistic approaches that combine targeted KRAS G12D inhibitors with immunotherapy agents. Preclinical studies have shown that combining a KRAS G12D inhibitor with immune checkpoint inhibitors can lead to improved tumor elimination and survival outcomes in models of pancreatic cancer. Ongoing clinical trials continue to advance effective treatments for KRAS G12D-mutated cancers.