As medical research progresses, remarkable strides continue to be made in cancer treatment. The American Association for Cancer Research (AACR) Annual Meeting, a globally renowned event, has long been a cornerstone in promoting innovation and development in oncology. With its extensive history, the AACR Annual Meeting is one of the most influential academic gatherings in the field, showcasing high-quality tumor research and addressing critical topics in oncology.
The 115th AACR Annual Meeting, held from April 5th to 10th, 2024, in the United States, featured 353 abstracts, with KRAS emerging as a prominent target for the first time, ranking among the top 15 targets in the 2024 abstracts.
Since its discovery over four decades ago, the KRAS gene has been recognized as a significant factor in human cancers. The initial mutation identified in bladder cancer underscored its complexity. The RAS gene family, comprising HRAS, KRAS, and NRAS, highlights KRAS as the most notable member.
KRAS mutations are among the most common oncogenic mutations, constituting approximately 85% of all RAS mutations. These mutations, including G12C, G12D, G12V, and pan-KRAS, are linked to various human diseases. In colorectal cancer (CRC), KRAS mutations are found in about 45% of U.S. cases and 49% of Chinese cases. Pancreatic ductal adenocarcinoma (PDAC) shows about 90% of U.S. cases and 89% of Chinese cases with KRAS mutations. Additionally, in lung adenocarcinoma (LUAD), 35% of U.S. cases and 13% of Chinese cases exhibit KRAS mutations. KRAS (G12C) mutations are particularly prevalent in LUAD, while KRAS (G12D) and KRAS (G12V) are common in CRC and PDAC.
Despite KRAS's critical importance, drug development targeting this gene has faced significant challenges, long deemed an "undruggable" target. These difficulties arise from KRAS protein's lack of hydrophobic pockets, high binding affinity with substrates, and the high intracellular concentration of GTP, complicating the development of competitive inhibitors.
The discovery of the KRAS G12C mutation, which substitutes glycine with cysteine at position 12, provided a breakthrough. This mutation offers a binding site for small molecule covalent inhibitors. Around 13% of non-small cell lung cancer patients and 3% of colorectal cancer patients have KRAS G12C mutations, highlighting the substantial impact of successful drug development in this area.
Following preclinical validation, several pharmaceutical companies have launched KRAS G12C inhibitors into clinical trials. Notable examples include AMG 510 (sotorasib) and MRTX849 (adagrasib), which have shown promising results in reducing tumor size in patients with KRAS G12C mutations. Additionally, combining MRTX849 with other treatments has enhanced anticancer activity in various tumor models.
Revolution Medicines' RMC-9805, a KRAS G12D inhibitor, demonstrates the potential to suppress tumor growth in animal models of PDAC and NSCLC. Currently undergoing Phase 1 clinical trials, RMC-9805 offers hope for treating solid tumors.
Verastem and GenFleet Therapeutics are developing GFH375/VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, showing efficacy in pancreatic and colorectal cancer models. Quanta Therapeutics' QTX3544, targeting KRAS G12V, and Frontier Medicines' FMC-376, a KRAS G12C inhibitor, also show promising results in preclinical studies.
KRAS's ability to exploit abnormal mutations in cancer cells presents ongoing challenges for drug development. However, new strategies and broad-spectrum KRAS inhibitors, including non-covalent inhibitors, offer new hope. As these innovative treatments enter clinical trials, they promise significant advancements in cancer treatment, providing new hope for patients worldwide.
The relentless pursuit of effective KRAS inhibitors underscores the dynamic nature of cancer research and the potential for groundbreaking therapies in the fight against cancer. Through continuous exploration and development, these new treatment strategies are poised to shine brightly in future clinical applications, bringing true relief to many suffering from this devastating disease.
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