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
BACKGROUND Patients with microsatellite stable(MSS)metastatic colorectal cancer(mCRC)typically exhibit an immunosuppressive tumor microenvironment and demonstrate a low response rate to immunotherapy.Reports suggest t...BACKGROUND Patients with microsatellite stable(MSS)metastatic colorectal cancer(mCRC)typically exhibit an immunosuppressive tumor microenvironment and demonstrate a low response rate to immunotherapy.Reports suggest that chemotherapy and anti-angiogenic therapy may have the potential to enhance the response to immunotherapy in these patients.This study aims to evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without antiprogrammed death 1(PD-1)immunotherapy as the second-line regimen for MSS mCRC.AIM To evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-PD-1 immunotherapy as the second-line regimen for MSS mCRC.METHODS A retrospective analysis was conducted on patients with MSS mCRC diagnosed at Peking University First Hospital and Jilin Cancer Hospital from January 2020 to December 2024.The patients were divided into two groups:The experimental group receiving second-line chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy,and the control group receiving chemotherapy combined with bevacizumab.Propensity score matching was applied to balance potential prognostic factors,including age,gender,Eastern Cooperative Oncology Group score,number of metastases,and primary tumor site.The progression-free survival,overall survival,disease control rate,objective response rate,and treatment-related adverse reactions were compared between the two groups.Kaplan-Meier analysis and log-rank test were used to compare survival outcomes.Inverse probability of treatment weighting was used for sensitivity analysis.RESULTS Propensity score matching resulted in 103 matched eligible patients.The median follow-up period was 13.9 months in the matched cohort.The objective response rate was 11.5%and 9%for the experimental and control groups,respectively(P=0.710),while the disease control rate was 76.9%and 53.2%,respectively(P=0.058).The median progression-free survival in the experimental group was 8.27 months[95%confidence interval(CI):6.7-14.7 months],significantly higher than that in the control group,which was 4.63 months(95%CI:3.9-5.67 months)(hazard ratio=0.4143,95%CI:0.2462-0.6972,P=0.00066).There was a trend towards the higher median overall survival in the experimental group compared to the control group(hazard ratio=0.4504,95%CI:0.1897-1.07,P=0.064).The incidences of adverse events were similar between the two groups.CONCLUSION Compared with the standard second-line chemotherapy combined with bevacizumab regimen,second-line therapy that combines chemotherapy with bevacizumab and anti-PD-1 immunotherapy has demonstrated promising efficacy in the treatment of MSS mCRC,while exhibiting a similar safety profile.展开更多
BACKGROUND Microsatellite stable(MSS)metastatic colorectal cancer(mCRC)is characterized by an immunosuppressive tumor microenvironment,leading to limited efficacy of immunotherapy in these patients.Clinical trial data...BACKGROUND Microsatellite stable(MSS)metastatic colorectal cancer(mCRC)is characterized by an immunosuppressive tumor microenvironment,leading to limited efficacy of immunotherapy in these patients.Clinical trial data suggest that chemotherapy and anti-angiogenic therapy may have the potential to enhance the response to immunotherapy in these patients.However,whether these research findings can be“replicated”in clinical practice still requires further validation through real-world studies.This study aims to evaluate the effectiveness and safety of chemo-therapy combined with bevacizumab with or without anti-programmed death 1(PD-1)immunotherapy as the first-line regimen for MSS mCRC in the real world.AIM To evaluate the effectiveness and safety of chemotherapy combined with beva-cizumab with or without anti-PD-1 immunotherapy as the first-line regimen for MSS mCRC in the real world.METHODS We conducted a retrospective analysis of patients with MSS mCRC diagnosed at Peking University First Hospital and Jilin Cancer Hospital between January 2020 and December 2024.Patients were stratified into two treatment groups:(1)An experimental group receiving first-line chemotherapy combined with bevaci-zumab and anti-PD-1 immunotherapy;and(2)A control group receiving chemo-therapy plus bevacizumab alone.Propensity score matching was employed to balance baseline characteristics,including age,gender,Eastern Cooperative Onco-logy Group performance status,number of metastatic sites,and primary tumor location.The primary endpoints were progression-free survival and overall survival,while secondary endpoints included disease control rate,objective response rate,and treatment-related adverse events.Survival outcomes were assessed using Kaplan-Meier analysis with log-rank testing.Additionally,inverse probability of treatment weighting was applied for sensitivity analysis to validate the robustness of our findings.RESULTS The propensity score matching analysis identified 103 well-balanced patient pairs with a median follow-up of 25.5 months.The experimental group demonstrated numerically higher objective response(36.00%vs 23.08%,P=0.309)and disease control rates(96.00%vs 91.03%,P=0.6759)compared to the control group,though these differences were not statistically significant.Similarly,no significant survival benefit was observed for either progression-free survival[hazard ratio(HR)=0.7076,95%confidence interval(CI):0.4069-1.23,P=0.22]or overall survival(HR=1.154,95%CI:0.4712-2.827,P=0.75).Multivariate analysis identified liver metastases as an independent poor prognostic factor(HR=3.36,95%CI:1.71-6.60,P<0.001),while subgroup analyses revealed potential benefits of the experimental regimen in male patients(HR=0.33,95%CI:0.14-0.81,P=0.025)and those with right-sided primary tumors(HR=0.40,95%CI:0.17-0.95,P=0.022).Safety profiles were comparable between groups,though elevated lactate dehydrogenase emerged as an independent risk factor for poorer outcomes in the experimental group(HR=4.11,95%CI:1.02-16.55,P=0.046).CONCLUSION Chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy could not demonstrate promising efficacy in treating MSS mCRC compared to the standard first-line chemotherapy regimen with bevacizumab.Male patients or those with right-sided mCRC may derive benefits from immune-based combination therapy.Further research is needed to investigate specific clinical characteristics or biomarkers to identify patients who may derive benefit from combined immunotherapy approaches.展开更多
BACKGROUND Metastatic colorectal cancer(mCRC)treatment has been evolving and increasingly driven by tumor biology and gene expression analysis.Rechallenge with epidermal growth factor receptor(EGFR)inhibitors(anti-EGF...BACKGROUND Metastatic colorectal cancer(mCRC)treatment has been evolving and increasingly driven by tumor biology and gene expression analysis.Rechallenge with epidermal growth factor receptor(EGFR)inhibitors(anti-EGFR)represents a promising strategy for patients with RAS wild-type(RAS-wt)mCRC and circulating tumor DNA has emerged as a potential selection strategy.Herein,we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge.CASE SUMMARY Our patient was diagnosed with stage IV RAS-wt,microsatellite-stable rectosigmoid junction adenocarcinoma.He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response,allowing for a left hepatectomy(R0),followed by post-operative chemotherapy and an anterior resection;progression-free survival(PFS)of 16 months was obtained.Due to hepatic and nodal relapse,second-line treatment with FOLFOX and bevacizumab was started with partial response;metastasectomy was performed(R0),achieving a PFS of 11 months.After a 15 months anti-EGFR-free interval,FOLFIRI and cetuximab were reintroduced upon disease progression,again with partial response and a PFS of 16 months.Following extensive hepatic relapse,cetuximab was reintroduced and a marked clinical and analytical improvement was seen,after only one cycle.RASwt status was confirmed on circulating tumor DNA.The patient’s overall survival exceeded 5 years.CONCLUSION Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.展开更多
BACKGROUND Patients harboring gene mutations like KRAS,NRAS,and BRAF demonstrate highly variable responses to chemotherapy,posing challenges for treatment optimization.Multiparametric magnetic resonance imaging(MRI),w...BACKGROUND Patients harboring gene mutations like KRAS,NRAS,and BRAF demonstrate highly variable responses to chemotherapy,posing challenges for treatment optimization.Multiparametric magnetic resonance imaging(MRI),with its noninvasive capability to assess tumor characteristics in detail,has shown promise in evaluating treatment response and predicting therapeutic outcomes.This technology holds potential for guiding personalized treatment strategies tailored to individual patient profiles,enhancing the precision and effectiveness of colorectal cancer care.AIM To create a multiparametric MRI-based predictive model for assessing chemotherapy efficacy in colorectal cancer patients with gene mutations.METHODS This retrospective study was conducted in a tertiary hospital,analyzing 157 colorectal cancer patients with gene mutations treated between August 2022 and December 2023.Based on chemotherapy outcomes,the patients were categorized into favorable(n=60)and unfavorable(n=50)response groups.Univariate and multivariate logistic regression analyses were performed to identify independent predictors of chemotherapy efficacy.A predictive nomogram was constructed using significant variables,and its performance was assessed using the area under the receiver operating characteristic curve(AUC)in both training and validation sets.RESULTS Univariate analysis identified that tumor differentiation,T2 signal intensity ratio,tumor-to-anal margin distance,and MRI-detected lymph node metastasis as significantly associated with chemotherapy response(P<0.05).Multivariate Logistics regression confirmed these four parameters as independent predictors.The predictive model demonstrated strong discrimination,with an AUC of 0.938(sensitivity:86%;specificity:92%)in the training set,and 0.942(sensitivity:100%;specificity:83%)in the validation set.CONCLUSION We established and validated a multiparametric MRI-based model for predicting chemotherapy response in colorectal cancer patients with gene mutations.This model holds promise for guiding individualized treatment strategies.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Supported by the National High Level Hospital Clinical Research Funding(Multi-center Clinical Research Project of Peking University First Hospital),No.2022CR65.
文摘BACKGROUND Patients with microsatellite stable(MSS)metastatic colorectal cancer(mCRC)typically exhibit an immunosuppressive tumor microenvironment and demonstrate a low response rate to immunotherapy.Reports suggest that chemotherapy and anti-angiogenic therapy may have the potential to enhance the response to immunotherapy in these patients.This study aims to evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without antiprogrammed death 1(PD-1)immunotherapy as the second-line regimen for MSS mCRC.AIM To evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-PD-1 immunotherapy as the second-line regimen for MSS mCRC.METHODS A retrospective analysis was conducted on patients with MSS mCRC diagnosed at Peking University First Hospital and Jilin Cancer Hospital from January 2020 to December 2024.The patients were divided into two groups:The experimental group receiving second-line chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy,and the control group receiving chemotherapy combined with bevacizumab.Propensity score matching was applied to balance potential prognostic factors,including age,gender,Eastern Cooperative Oncology Group score,number of metastases,and primary tumor site.The progression-free survival,overall survival,disease control rate,objective response rate,and treatment-related adverse reactions were compared between the two groups.Kaplan-Meier analysis and log-rank test were used to compare survival outcomes.Inverse probability of treatment weighting was used for sensitivity analysis.RESULTS Propensity score matching resulted in 103 matched eligible patients.The median follow-up period was 13.9 months in the matched cohort.The objective response rate was 11.5%and 9%for the experimental and control groups,respectively(P=0.710),while the disease control rate was 76.9%and 53.2%,respectively(P=0.058).The median progression-free survival in the experimental group was 8.27 months[95%confidence interval(CI):6.7-14.7 months],significantly higher than that in the control group,which was 4.63 months(95%CI:3.9-5.67 months)(hazard ratio=0.4143,95%CI:0.2462-0.6972,P=0.00066).There was a trend towards the higher median overall survival in the experimental group compared to the control group(hazard ratio=0.4504,95%CI:0.1897-1.07,P=0.064).The incidences of adverse events were similar between the two groups.CONCLUSION Compared with the standard second-line chemotherapy combined with bevacizumab regimen,second-line therapy that combines chemotherapy with bevacizumab and anti-PD-1 immunotherapy has demonstrated promising efficacy in the treatment of MSS mCRC,while exhibiting a similar safety profile.
基金Supported by the National High Level Hospital Clinical Research Funding(Multi-Center Clinical Research Project of Peking University First Hospital),No.2022CR65.
文摘BACKGROUND Microsatellite stable(MSS)metastatic colorectal cancer(mCRC)is characterized by an immunosuppressive tumor microenvironment,leading to limited efficacy of immunotherapy in these patients.Clinical trial data suggest that chemotherapy and anti-angiogenic therapy may have the potential to enhance the response to immunotherapy in these patients.However,whether these research findings can be“replicated”in clinical practice still requires further validation through real-world studies.This study aims to evaluate the effectiveness and safety of chemo-therapy combined with bevacizumab with or without anti-programmed death 1(PD-1)immunotherapy as the first-line regimen for MSS mCRC in the real world.AIM To evaluate the effectiveness and safety of chemotherapy combined with beva-cizumab with or without anti-PD-1 immunotherapy as the first-line regimen for MSS mCRC in the real world.METHODS We conducted a retrospective analysis of patients with MSS mCRC diagnosed at Peking University First Hospital and Jilin Cancer Hospital between January 2020 and December 2024.Patients were stratified into two treatment groups:(1)An experimental group receiving first-line chemotherapy combined with bevaci-zumab and anti-PD-1 immunotherapy;and(2)A control group receiving chemo-therapy plus bevacizumab alone.Propensity score matching was employed to balance baseline characteristics,including age,gender,Eastern Cooperative Onco-logy Group performance status,number of metastatic sites,and primary tumor location.The primary endpoints were progression-free survival and overall survival,while secondary endpoints included disease control rate,objective response rate,and treatment-related adverse events.Survival outcomes were assessed using Kaplan-Meier analysis with log-rank testing.Additionally,inverse probability of treatment weighting was applied for sensitivity analysis to validate the robustness of our findings.RESULTS The propensity score matching analysis identified 103 well-balanced patient pairs with a median follow-up of 25.5 months.The experimental group demonstrated numerically higher objective response(36.00%vs 23.08%,P=0.309)and disease control rates(96.00%vs 91.03%,P=0.6759)compared to the control group,though these differences were not statistically significant.Similarly,no significant survival benefit was observed for either progression-free survival[hazard ratio(HR)=0.7076,95%confidence interval(CI):0.4069-1.23,P=0.22]or overall survival(HR=1.154,95%CI:0.4712-2.827,P=0.75).Multivariate analysis identified liver metastases as an independent poor prognostic factor(HR=3.36,95%CI:1.71-6.60,P<0.001),while subgroup analyses revealed potential benefits of the experimental regimen in male patients(HR=0.33,95%CI:0.14-0.81,P=0.025)and those with right-sided primary tumors(HR=0.40,95%CI:0.17-0.95,P=0.022).Safety profiles were comparable between groups,though elevated lactate dehydrogenase emerged as an independent risk factor for poorer outcomes in the experimental group(HR=4.11,95%CI:1.02-16.55,P=0.046).CONCLUSION Chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy could not demonstrate promising efficacy in treating MSS mCRC compared to the standard first-line chemotherapy regimen with bevacizumab.Male patients or those with right-sided mCRC may derive benefits from immune-based combination therapy.Further research is needed to investigate specific clinical characteristics or biomarkers to identify patients who may derive benefit from combined immunotherapy approaches.
文摘BACKGROUND Metastatic colorectal cancer(mCRC)treatment has been evolving and increasingly driven by tumor biology and gene expression analysis.Rechallenge with epidermal growth factor receptor(EGFR)inhibitors(anti-EGFR)represents a promising strategy for patients with RAS wild-type(RAS-wt)mCRC and circulating tumor DNA has emerged as a potential selection strategy.Herein,we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge.CASE SUMMARY Our patient was diagnosed with stage IV RAS-wt,microsatellite-stable rectosigmoid junction adenocarcinoma.He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response,allowing for a left hepatectomy(R0),followed by post-operative chemotherapy and an anterior resection;progression-free survival(PFS)of 16 months was obtained.Due to hepatic and nodal relapse,second-line treatment with FOLFOX and bevacizumab was started with partial response;metastasectomy was performed(R0),achieving a PFS of 11 months.After a 15 months anti-EGFR-free interval,FOLFIRI and cetuximab were reintroduced upon disease progression,again with partial response and a PFS of 16 months.Following extensive hepatic relapse,cetuximab was reintroduced and a marked clinical and analytical improvement was seen,after only one cycle.RASwt status was confirmed on circulating tumor DNA.The patient’s overall survival exceeded 5 years.CONCLUSION Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.
基金Supported by Shenzhen High-level Hospital Construction Fund.
文摘BACKGROUND Patients harboring gene mutations like KRAS,NRAS,and BRAF demonstrate highly variable responses to chemotherapy,posing challenges for treatment optimization.Multiparametric magnetic resonance imaging(MRI),with its noninvasive capability to assess tumor characteristics in detail,has shown promise in evaluating treatment response and predicting therapeutic outcomes.This technology holds potential for guiding personalized treatment strategies tailored to individual patient profiles,enhancing the precision and effectiveness of colorectal cancer care.AIM To create a multiparametric MRI-based predictive model for assessing chemotherapy efficacy in colorectal cancer patients with gene mutations.METHODS This retrospective study was conducted in a tertiary hospital,analyzing 157 colorectal cancer patients with gene mutations treated between August 2022 and December 2023.Based on chemotherapy outcomes,the patients were categorized into favorable(n=60)and unfavorable(n=50)response groups.Univariate and multivariate logistic regression analyses were performed to identify independent predictors of chemotherapy efficacy.A predictive nomogram was constructed using significant variables,and its performance was assessed using the area under the receiver operating characteristic curve(AUC)in both training and validation sets.RESULTS Univariate analysis identified that tumor differentiation,T2 signal intensity ratio,tumor-to-anal margin distance,and MRI-detected lymph node metastasis as significantly associated with chemotherapy response(P<0.05).Multivariate Logistics regression confirmed these four parameters as independent predictors.The predictive model demonstrated strong discrimination,with an AUC of 0.938(sensitivity:86%;specificity:92%)in the training set,and 0.942(sensitivity:100%;specificity:83%)in the validation set.CONCLUSION We established and validated a multiparametric MRI-based model for predicting chemotherapy response in colorectal cancer patients with gene mutations.This model holds promise for guiding individualized treatment strategies.
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.
