Research progress in the related treatment of KRAS mutant colorectal cancer

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a type of gene closely related to human tumors. And it’s an important medical index to access the tumor development, prognosis and the efficacy of chemoradiotherapy. RAS mutations, in which KRAS mutations account for up to 85%, are the most common oncogenic driving mutations in human tumors. The most frequent KRAS mutation sites are codons 12, 13, 61 and 146. Codon G12, as the most frequently mutated one, can be divided into multiple subtypes, with G12D mutation being the most common, followed by G12V, G12C, etc. Colorectal cancer (CRC) is one of the tumors with the highest frequency of KRAS mutations. Both G12D and G12V are the most common mutation subtypes in CRC. In the field of treatments for CRC with KRAS mutations, targeted therapy had not been possible until the release of KRASG12C inhibitors in 2013, and new drugs have been developed one after another since then. This study summarized the mutations of KRAS and the advances in clinical research, including the latest advances in targeted drugs, chemotherapy drugs, immunotherapy drugs, ferroptosis, and other treatment methods. Among them, in terms of targeted drugs, this review explored KRASG12C inhibitors (sotorasib, adagrasib, D-1553, IBI351, etc.), anti-angiogenic drugs (monoclonal antibodies such as bevacizumab, remdesizumab, etc), small molecule multi-target tyrosine kinase inhibitors such as sunitinib, etc. In terms of immunotherapy drugs, there have also been many advances, such as the ARETHUSA clinical trial, which found that temozolomide reduced the tumor mutational burden (TMB) of O-6-methylguanine-DNA methyltransferase (MGMT) deficiency and RAS mutation in patients with advanced metastatic colorectal cancer (mCRC), providing innovative ideas for patient immunotherapy. For example, the combination of xindilimab with bevacizumab, oxaliplatin, and capecitabine can be used for first-line treatment of RAS mutations, microsatellite stability (MSS), and unresectable mCRC. Relevant studies have shown that the combination therapy has good therapeutic potential and controllable tolerability safety. This review explored the mechanisms of KRAS mutations and the latest advances in clinical research and treatment, in order to provide reference for the treatment of KRAS mutated colorectal cancer.

Keywords

• |kirsten rats arcomaviral oncogene homolog|colorectal cancer|medication