More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but s...More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.展开更多
BACKGROUND Lung cancer is increasing in incidence worldwide,and targeted therapies are developing at a rapid pace.Furthermore,the KRAS specific gene is strongly associated with non-small cell lung cancer(NSCLC).Adult ...BACKGROUND Lung cancer is increasing in incidence worldwide,and targeted therapies are developing at a rapid pace.Furthermore,the KRAS specific gene is strongly associated with non-small cell lung cancer(NSCLC).Adult patients with locally advanced or metastatic NSCLC who have tested positive for the KRAS G12C mutation and have progressed after at least one systemic treatment are treated with sotorasib.CASE SUMMARY In this study,we report on an advanced NSCLC with a KRAS G12C mutation.The histological diagnosis indicates stage IVB left lung adenocarcinoma with pelvic and bone metastases,identified as cT4N2bM1c.Using circulating tumor DNA analysis,it was possible to determine the mutation abundance of the KRAS gene exon 2,c.34G>Tp.G12C,which was 32.3%.The patient was advised to take sotorasib as part of their treatment.The imaging data were compared before and after treatment.Furthermore,clinical reassessments and regular serial blood testing were conducted.We found that the patient’s clinical symptoms significantly improved after receiving sotorasib medication,and there were no notable side effects,such as liver toxicity,during the treatment.CONCLUSION Sotorasib has shown promising clinical efficacy in patients with the KRAS G12c mutation and has no apparent toxic side effects.展开更多
Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexp...Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs i展开更多
With the advent of Kirsten rat sarcoma viral oncogene homologue G12C(KRAS G12C)inhibitors,RAS is no longer considered undruggable.For the suppression of RAS,new therapeutic approaches have been suggested.However,curre...With the advent of Kirsten rat sarcoma viral oncogene homologue G12C(KRAS G12C)inhibitors,RAS is no longer considered undruggable.For the suppression of RAS,new therapeutic approaches have been suggested.However,current clinical studies have indicated therapeutic resistance after short-lived tumour suppression.According to preclinical studies,this might be associated with acquired genetic alterations,reactivation of downstream pathways,and stimulation for upstream signalling.In this review,we aimed to summarize current approaches for combination therapy to alleviate resistance to KRAS G12C inhibitors in colorectal cancer with a focus on the mechanisms of therapeutic resistance.We also analysed the relationship between various mechanisms and therapeutic resistance.展开更多
KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging.Among the different known mutants,KRas^(G12C) has been proved to be successfully targete...KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging.Among the different known mutants,KRas^(G12C) has been proved to be successfully targeted recently.Several covalent inhibitors selectively targeting KRas^(G12C) have shown promising efficacy against cancers harboring KRAS G12C mutation in clinical trials and AMG510(sotorasib)has been approved for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.However,the overall responsive rate of KRas^(G12C) inhibitors was around 50%in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable.It is of great importance to discover biomarkers to distinguish patients who are likely benefitted.Moreover,adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies.Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^(G12C) inhibitors in preclinical settings.This review summarized the recent progress of covalent KRas^(G12C) inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.展开更多
文摘More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.
文摘BACKGROUND Lung cancer is increasing in incidence worldwide,and targeted therapies are developing at a rapid pace.Furthermore,the KRAS specific gene is strongly associated with non-small cell lung cancer(NSCLC).Adult patients with locally advanced or metastatic NSCLC who have tested positive for the KRAS G12C mutation and have progressed after at least one systemic treatment are treated with sotorasib.CASE SUMMARY In this study,we report on an advanced NSCLC with a KRAS G12C mutation.The histological diagnosis indicates stage IVB left lung adenocarcinoma with pelvic and bone metastases,identified as cT4N2bM1c.Using circulating tumor DNA analysis,it was possible to determine the mutation abundance of the KRAS gene exon 2,c.34G>Tp.G12C,which was 32.3%.The patient was advised to take sotorasib as part of their treatment.The imaging data were compared before and after treatment.Furthermore,clinical reassessments and regular serial blood testing were conducted.We found that the patient’s clinical symptoms significantly improved after receiving sotorasib medication,and there were no notable side effects,such as liver toxicity,during the treatment.CONCLUSION Sotorasib has shown promising clinical efficacy in patients with the KRAS G12c mutation and has no apparent toxic side effects.
基金supported by a Spanish Association Against Cancer(AECC)grant,(grant No.PROYE18012ROSE)support from Julián Santamaría Vali?o to the IOR Foundation。
文摘Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs i
文摘With the advent of Kirsten rat sarcoma viral oncogene homologue G12C(KRAS G12C)inhibitors,RAS is no longer considered undruggable.For the suppression of RAS,new therapeutic approaches have been suggested.However,current clinical studies have indicated therapeutic resistance after short-lived tumour suppression.According to preclinical studies,this might be associated with acquired genetic alterations,reactivation of downstream pathways,and stimulation for upstream signalling.In this review,we aimed to summarize current approaches for combination therapy to alleviate resistance to KRAS G12C inhibitors in colorectal cancer with a focus on the mechanisms of therapeutic resistance.We also analysed the relationship between various mechanisms and therapeutic resistance.
基金supported by the National Natural Science Foundation of China(No.81773760,81973345,and 82104199).
文摘KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging.Among the different known mutants,KRas^(G12C) has been proved to be successfully targeted recently.Several covalent inhibitors selectively targeting KRas^(G12C) have shown promising efficacy against cancers harboring KRAS G12C mutation in clinical trials and AMG510(sotorasib)has been approved for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.However,the overall responsive rate of KRas^(G12C) inhibitors was around 50%in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable.It is of great importance to discover biomarkers to distinguish patients who are likely benefitted.Moreover,adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies.Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^(G12C) inhibitors in preclinical settings.This review summarized the recent progress of covalent KRas^(G12C) inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.
