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2. Research progress in the related treatment of KRAS mutant colorectal cancer

Author

ZHANG Shaohua, LI Zhening, WANG Wei, WEI Yifan, HONG Yonggang, HAO Liqiang

Subjects
kirsten rats arcomaviral oncogene homolog, colorectal cancer, medication, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
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.

Published
2024
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28. Effects of Fat and Carbohydrate Energy Supply Ratio on Fat Metabolism and Intestinal Microbiota in Rats

Author

WANG Wei-wei, YANG Ying, WANG Li, SONG Dan, and LI Ai-ke

Subjects
fat and carbohydrate energy supply ratio, fat metabolism, intestinal microbiota, rat, Food processing and manufacture, TP368-456, Nutrition. Foods and food supply, TX341-641
Abstract

The proportions of fat and carbohydrate in diet have an important impact on lipid metabolism, glucose metabolism and health. On the premise of consistent dietary available energy (metabolic energy), the effects of different fat and carbohydrates energy supply ratios in diet on fat metabolism and gut microbiota were studied. Sixty-four 9-weeks-old SPF grade male SD rats aged 9 weeks were randomly divided into 4 groups including: HFf group (energy supply ratio of fat to carbohydrate (F/C) 40% : 45%), MFf group (F/C 31% : 54%), LFf group (F/C 21% : 64%) and CON group (control diet). The results showed that there were no significant differences in body weight, blood glucose, blood lipid and liver steatosis among all groups (P > 0.05). The liver triglyceride and abdominal adiponectin of HFf group were significantly higher than those of the other three groups (P < 0.05). Compared to the CON group, the acetyl-CoA carboxylase (ACC) gene expression in the liver of HFf group decreased, while the expressions of lipid synthesis genes, fatty acid transporter (FAT/CD36), sterol regulatory element binding protein (SREBP1), and adipocyte differentiation gene peroxisome proliferator-activated receptor (PPARγ) increased in HFf group (P < 0.05). Compared with CON group, the cholesterol synthesis factor hydroxymethylglutarate monoacyl CoA (HMG-CoA) gene expression in the liver of HFf, MFf and LFf groups were all increased (P < 0.05). In addition, the higher dietary F/C (40% : 45% and 30% : 55%) resulted in impaired gut villi development, which led to decreasing abundance of beneficial bacteria but increasing abundance of potentially pathogenic bacteria. In conclusion, under the same dietary available energy, although the diet of the high-fat group contained a high proportion of fat, it also contained a high content of cellulose, which effectively alleviated the weight gain and blood glucose and lipid abnormalities caused by the high-fat diet. However, there were still symptoms such as increased liver fat and impaired intestinal health, and the F/C in the diet of rats should not exceed 30%. This provides a theoretical reference for the appropriate proportion of macronutrients in the diet.

Published
2023
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