Abnormality of ras gene family was studied in a total of 206 cases of gastric cancer and precancerous lesions by PCR-RFLP, PCR-SSCP and DNA sequencing. The results showed that mutation rate of H-ras 12 codon in metapl...Abnormality of ras gene family was studied in a total of 206 cases of gastric cancer and precancerous lesions by PCR-RFLP, PCR-SSCP and DNA sequencing. The results showed that mutation rate of H-ras 12 codon in metaplasia,atypical hyperplasia, early-stage cancer and advanced cancer was 16. 7%, 31. 2 %, 50. 0%, and 32. 2%, respectively. In the groups of superficial gastritis and normal controls, no mutation were detected in codon 12 of ras. Mutations of Hras 61 codon and N-ras 12 codon in various groups were the same as those in normal control. K-ras 12 codon mutation was detected in only 2 cases of gastric cancer by using PCR-SSCP, but it was not detected by DNA sequencing, which may be polymorphism. All H-ras 12 codon mutations were G→T mutation. There were significant difference between the groups of metaplasia, dysplasia, gastric carcinoma and normal control group (P<0.05, P<0.01, P<0.01,respectively). It was concluded that H-ras 12 codon mutation was an early event and may play an important role in gastric carcinogenesis. Although K-ras, N-ras mutation rates are high in colon cancer and leukemia, it seems to bear no relationship with gastric cancer.展开更多
RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack...RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF kinases.First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade.However,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization.To address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading candidates.Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors.Promisingly,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors.This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.展开更多
RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending ...RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending on the tissue types.Despite decades of developing RAS-targeted therapies,only small subsets of these inhibitors are clinically effective,such as the allelespecific inhibitors against KRASG12C.Targeting the remaining RAS mutants would require further experimental elucidation ofRAS signal transduction,RASaltered metabolism,and the associated immune microenvironment.This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants,including KRAS allele-specific inhibitors,combination therapies,immunotherapies,and metabolism-associated therapies.展开更多
文摘Abnormality of ras gene family was studied in a total of 206 cases of gastric cancer and precancerous lesions by PCR-RFLP, PCR-SSCP and DNA sequencing. The results showed that mutation rate of H-ras 12 codon in metaplasia,atypical hyperplasia, early-stage cancer and advanced cancer was 16. 7%, 31. 2 %, 50. 0%, and 32. 2%, respectively. In the groups of superficial gastritis and normal controls, no mutation were detected in codon 12 of ras. Mutations of Hras 61 codon and N-ras 12 codon in various groups were the same as those in normal control. K-ras 12 codon mutation was detected in only 2 cases of gastric cancer by using PCR-SSCP, but it was not detected by DNA sequencing, which may be polymorphism. All H-ras 12 codon mutations were G→T mutation. There were significant difference between the groups of metaplasia, dysplasia, gastric carcinoma and normal control group (P<0.05, P<0.01, P<0.01,respectively). It was concluded that H-ras 12 codon mutation was an early event and may play an important role in gastric carcinogenesis. Although K-ras, N-ras mutation rates are high in colon cancer and leukemia, it seems to bear no relationship with gastric cancer.
基金This study was supported by the National Natural Science Foundation of China(82073059,82073314)the Sichuan Science and Technology Program(2023NSFSC1838,China)the Sichuan University Postdoctoral Interdisciplinary Innovation Fund(JCXK2212,China).
文摘RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF kinases.First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade.However,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization.To address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading candidates.Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors.Promisingly,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors.This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.
基金National Natural Science Foundation of China,Grant/Award Numbers:82072360,82102704,82072624,81872481Natural Science Foundation of Zhejiang Province,Grant/Award Number:LBY20H160002。
文摘RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending on the tissue types.Despite decades of developing RAS-targeted therapies,only small subsets of these inhibitors are clinically effective,such as the allelespecific inhibitors against KRASG12C.Targeting the remaining RAS mutants would require further experimental elucidation ofRAS signal transduction,RASaltered metabolism,and the associated immune microenvironment.This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants,including KRAS allele-specific inhibitors,combination therapies,immunotherapies,and metabolism-associated therapies.