Objective:To investigate the effect and mechanism of inhibitor everolimus on EGFR-TKI resistance NSCLC.Methods:MTT assay was used to detect proliferation of human non-small cell lung cancer cell line A549.Flow cytomet...Objective:To investigate the effect and mechanism of inhibitor everolimus on EGFR-TKI resistance NSCLC.Methods:MTT assay was used to detect proliferation of human non-small cell lung cancer cell line A549.Flow cytometry was used to detect the changes of apoptosis and cycle distribution in each group after 24 h and 48 h.RT-PCR was used to detect the changes of PTEN and 4EBP1 expression levels after 48 h of monotherapy and combination therapy.Results:MTT assay showed that everolimus had dose-dependent inhibition against growth of A549 cells.Flow cytometry showed when everolimus could induce apoptosis and induce G0/G1 phase cell cycle arrest,which was time-dependent(P<0.05).RT-PCR showed everolimus could increase PTEN and 4EBP1 expression.Conclusions:mTOR inhibitor everolimus has an inhibitory effect on EGFR-TKI resistant NSCLC,which cannot reverse the resistance effect of EGFR-TKI resistant cell line A549.The relationship between EGFR/AKT signaling pathway and the mTOR signaling pathway and the mechanism in non-small cell lung cancer need further study.展开更多
Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harbo...Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.展开更多
Existing studies have yet to elucidate clearly the mechanisms of secondary resistance to third generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),neither is there any established standar...Existing studies have yet to elucidate clearly the mechanisms of secondary resistance to third generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),neither is there any established standard therapy for patients resistant to third generation EGFR-TKIs.This case report demonstrates a rare mutation pattern in a male patient with a pathologic diagnosis of non-small cell lung cancer(NSCLC)harboring an EGFR exon 19 deletion(19Del)mutation,who then acquired an EGFR-T790M mutation after developing resistance to the first generation EGFR-TKI(gefitinib).The mutation reverted to the original EGFR-19Del mutation after the patient developed secondary resistance against the third generation TKI(osimertinib).This patient eventually achieved partial response(PR)with second generation TKI(afatinib)as a fourth-line treatment.展开更多
Oncogenic activation of the fibroblast growth factor receptor(FGFR)through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and cholangiocarcinoma.Inhibi...Oncogenic activation of the fibroblast growth factor receptor(FGFR)through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and cholangiocarcinoma.Inhibition of the kinase domain of the FGFR with targeted oral FGFR inhibitors has been shown in both preclinical and early phase clinical trials to lead to meaningful reductions in tumour size and larger confirmatory randomized trials are underway.Acquired resistance to FGFR inhibition using a variety of mechanisms that includes,activation of alternate signaling pathways and expansion of tumour clones with gatekeeper mutations in the FGFR gene.This review summarizes the acquired resistance mechanisms to FGFR therapy and therapeutic approaches to circumventing resistance.展开更多
The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(...The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),has revolutionized the treatment of this frequently occurring lung malignancy.Indeed,the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy.Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC).The first-generation TKIs include erlotinib,gefitinib,lapatinib,and icotinib;the second-generation ErbB family blockers include afatinib,neratinib,and dacomitinib;whereas osimertinib,approved by the FDA on 2015,is a third-generation TKI targeting EGFR harboring specific mutations.Compared with the first-and second-generation TKIs,third-generation EGFR inhibitors display a significant advantage in terms of patient survival.For example,the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months.Unfortunately,however,like other targeted therapies,new EGFR mutations,as well as additional drug-resistance mechanisms emerge rapidly after treatment,posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance.In this review,we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance.We also discuss the current status of fourthgeneration EGFR inhibitors,which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.展开更多
Gallbladder cancer(GBC)is a highly invasive disease and the most prevalent malignancy of the biliary system.Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis.Palliative chemoth...Gallbladder cancer(GBC)is a highly invasive disease and the most prevalent malignancy of the biliary system.Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis.Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades.Recently,several targeted therapies have been investigated in advanced biliary tract cancer(BTC)including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements,IDH1 mutations,and NTRK gene fusions.Also,several clinical studies involving molecular stratification have been performed in defined patient groups,for example,BRAF V600E and HER2.Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene.Targeting the MET signaling pathway is an effective strategy in numerous cancer types.However,the poor efficacy of MET inhibitors has been demonstrated in several phase II studies,but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC.In this article,we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy.After the patient had progressed and discontinued crizotinib,cabozantinib was introduced.Analysis of circulating tumor DNA(ctDNA)by nextgeneration sequencing(NGS)indicated a loss of MET amplification status.To our knowledge,this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.展开更多
Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs),most advanced non-small-cell lung cancers(NSCLCs)progress eventually due to therapeutic resis...Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs),most advanced non-small-cell lung cancers(NSCLCs)progress eventually due to therapeutic resistance.V-Raf murine sarcoma viral oncogene homolog B1(BRAF)^(V600E) mutation has been considered as an uncommon mutation that contributes to acquired resistance for EGFR-TKIs.In the presented case,BRAF^(V600E) mutation was detected as an acquired resistance-mediated mutation in a patient treated with osimertinib(a third-generation EGFR-TKI).The presented patient achieved partial regression and ongoing PFS of four months after the co-inhibition of osimertinib plus dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor).Our case further enriches the clinical evidence of the efficacy of EGFR/BRAF/MEK co-inhibition in patients with an acquired BRAF^(V600E) mutation,consistent with the review of the literature(eight cases).Additionally,our case highlights the important role of sample type,method,and platform of gene detection in patient management,life quality,and prognosis,as well as the understanding of acquired resistance mechanism.展开更多
基金supported by Science and Technology Planning Project of Society Development in Yunan Province(2010CA015)
文摘Objective:To investigate the effect and mechanism of inhibitor everolimus on EGFR-TKI resistance NSCLC.Methods:MTT assay was used to detect proliferation of human non-small cell lung cancer cell line A549.Flow cytometry was used to detect the changes of apoptosis and cycle distribution in each group after 24 h and 48 h.RT-PCR was used to detect the changes of PTEN and 4EBP1 expression levels after 48 h of monotherapy and combination therapy.Results:MTT assay showed that everolimus had dose-dependent inhibition against growth of A549 cells.Flow cytometry showed when everolimus could induce apoptosis and induce G0/G1 phase cell cycle arrest,which was time-dependent(P<0.05).RT-PCR showed everolimus could increase PTEN and 4EBP1 expression.Conclusions:mTOR inhibitor everolimus has an inhibitory effect on EGFR-TKI resistant NSCLC,which cannot reverse the resistance effect of EGFR-TKI resistant cell line A549.The relationship between EGFR/AKT signaling pathway and the mTOR signaling pathway and the mechanism in non-small cell lung cancer need further study.
文摘Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.
基金supported by the National Natural Science Foundation of China(Grant No.81673032).
文摘Existing studies have yet to elucidate clearly the mechanisms of secondary resistance to third generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),neither is there any established standard therapy for patients resistant to third generation EGFR-TKIs.This case report demonstrates a rare mutation pattern in a male patient with a pathologic diagnosis of non-small cell lung cancer(NSCLC)harboring an EGFR exon 19 deletion(19Del)mutation,who then acquired an EGFR-T790M mutation after developing resistance to the first generation EGFR-TKI(gefitinib).The mutation reverted to the original EGFR-19Del mutation after the patient developed secondary resistance against the third generation TKI(osimertinib).This patient eventually achieved partial response(PR)with second generation TKI(afatinib)as a fourth-line treatment.
基金Lau DK received financial support from La Trobe University(Australian Postgraduate Award),Pancare/RMA NetworkJenkins L received financial support from La Trobe University(Australian Postgraduate Award)Weickhardt A has received consulting fees from Merck,Novartis,Pfizer and Ipsen.
文摘Oncogenic activation of the fibroblast growth factor receptor(FGFR)through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and cholangiocarcinoma.Inhibition of the kinase domain of the FGFR with targeted oral FGFR inhibitors has been shown in both preclinical and early phase clinical trials to lead to meaningful reductions in tumour size and larger confirmatory randomized trials are underway.Acquired resistance to FGFR inhibition using a variety of mechanisms that includes,activation of alternate signaling pathways and expansion of tumour clones with gatekeeper mutations in the FGFR gene.This review summarizes the acquired resistance mechanisms to FGFR therapy and therapeutic approaches to circumventing resistance.
基金The study was supported by the Natural Science Foundation of Shanghai(No.20ZR1410400)the Extraordinary 2025 Elite Project of Fudan University,the National Natural Science Foundation of China(No.81772590 and 81572395)+1 种基金the Open Funding of Key Laboratory of Diagnosis and Treatment of Severe Hepato-pancreatic Diseases of Zhejiang Province(No.2018E10008)the CAS Interdisciplinary Innovation Team JCTD-2019-07.All figures showing EGFR kinase structure and binding modes were generated using PyMol 2.4.1(www.pymol.org).
文摘The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),has revolutionized the treatment of this frequently occurring lung malignancy.Indeed,the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy.Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC).The first-generation TKIs include erlotinib,gefitinib,lapatinib,and icotinib;the second-generation ErbB family blockers include afatinib,neratinib,and dacomitinib;whereas osimertinib,approved by the FDA on 2015,is a third-generation TKI targeting EGFR harboring specific mutations.Compared with the first-and second-generation TKIs,third-generation EGFR inhibitors display a significant advantage in terms of patient survival.For example,the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months.Unfortunately,however,like other targeted therapies,new EGFR mutations,as well as additional drug-resistance mechanisms emerge rapidly after treatment,posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance.In this review,we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance.We also discuss the current status of fourthgeneration EGFR inhibitors,which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.
基金This work was supported by the National Key Development Plan for Precision Medicine Research(Grant No.2017YFC0910004).
文摘Gallbladder cancer(GBC)is a highly invasive disease and the most prevalent malignancy of the biliary system.Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis.Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades.Recently,several targeted therapies have been investigated in advanced biliary tract cancer(BTC)including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements,IDH1 mutations,and NTRK gene fusions.Also,several clinical studies involving molecular stratification have been performed in defined patient groups,for example,BRAF V600E and HER2.Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene.Targeting the MET signaling pathway is an effective strategy in numerous cancer types.However,the poor efficacy of MET inhibitors has been demonstrated in several phase II studies,but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC.In this article,we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy.After the patient had progressed and discontinued crizotinib,cabozantinib was introduced.Analysis of circulating tumor DNA(ctDNA)by nextgeneration sequencing(NGS)indicated a loss of MET amplification status.To our knowledge,this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.
基金This work was supported by the Shanghai Municipal Key Clinical Specialty(shslczdzk02202)the National Natural Science Foundation of China(81672271).
文摘Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs),most advanced non-small-cell lung cancers(NSCLCs)progress eventually due to therapeutic resistance.V-Raf murine sarcoma viral oncogene homolog B1(BRAF)^(V600E) mutation has been considered as an uncommon mutation that contributes to acquired resistance for EGFR-TKIs.In the presented case,BRAF^(V600E) mutation was detected as an acquired resistance-mediated mutation in a patient treated with osimertinib(a third-generation EGFR-TKI).The presented patient achieved partial regression and ongoing PFS of four months after the co-inhibition of osimertinib plus dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor).Our case further enriches the clinical evidence of the efficacy of EGFR/BRAF/MEK co-inhibition in patients with an acquired BRAF^(V600E) mutation,consistent with the review of the literature(eight cases).Additionally,our case highlights the important role of sample type,method,and platform of gene detection in patient management,life quality,and prognosis,as well as the understanding of acquired resistance mechanism.
