In the present study,we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition(EMT)and angiogenesis.In a clinical case,anlotinib reverse...In the present study,we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition(EMT)and angiogenesis.In a clinical case,anlotinib reversed osimertinib resistance in non-small cell lung cancer(NSCLC).Therefore,we performed immunohistochemical analyses on tumor tissues from three NSCLC patients with osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A(VEGFA)before and after the development of osimertinib resistance.The results revealed the downregulation of E-cadherin,coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance,compared with those in tissues from patients before receiving osimertinib.Subsequently,we established osimertinib-resistant(Osi-R)cell lines and found that the Osi-R cells acquired EMT features.Next,we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT.The expression levels of VEGFA and tube formation were analyzed in the combination group in vitro.Finally,we determined the reversal of osimertinib resistance by the combination of osimertinib and anlotinib in vivo using 20 nude mice.The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of Osi-R cells,inhibited tumor growth,exerted antitumor activity,and ultimately reversed osimertinib resistance in mice.The co-administration of osimertinib and anlotinib demonstrated synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients,ultimately reversing osimertinib resistance.展开更多
BACKGROUND Most non-small cell lung cancer patients have epidermal growth factor receptor(EGFR)activating mutations,such as exon 19 deletion and exon 21 replacement mutations.Osimertinib is a third-generation EGFR-tyr...BACKGROUND Most non-small cell lung cancer patients have epidermal growth factor receptor(EGFR)activating mutations,such as exon 19 deletion and exon 21 replacement mutations.Osimertinib is a third-generation EGFR-tyrosine kinase inhibitors ap-proved for the treatment of lung cancer patients carrying EGFR activating mu-tations.Osimertinib-induced interstitial lung disease(ILD)is a rare and poten-tially fatal pulmonary toxic manifestation of drug therapy.At present,there is no international consensus on the risks and treatment of the osimertinib-induced ILD.CASE SUMMARY We report a case of a 56-year-old woman who was diagnosed with lung adenocar-cinoma with lung hilum,mediastinal lymph nodes and brain metastases(T4N3-M1c stage IVB).The patient received targeted treatment with osimertinib after radiotherapy and chemotherapy.But she developed ILD after osimertinib treat-ment.Following active symptomatic treatment and hormone treatment,the lung injury alleviated.The patient was retreated with furmonertinib combined with prednisone and did not experience ILD again.So far,she has survived for 14 months without disease progression.CONCLUSION Retreatment with furmonertinib under prednisone could be considered as an effective therapeutic option after risk-benefit assessment for EGFR-mutant lung adenocarcinoma patients.展开更多
Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination str...Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.展开更多
Objective:The combination of epithelial growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)and immune checkpoint inhibitors(ICIs)leads to an increased incidence of severe immune-related adverse events(irAEs)....Objective:The combination of epithelial growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)and immune checkpoint inhibitors(ICIs)leads to an increased incidence of severe immune-related adverse events(irAEs).However,the mechanisms underlying macrophages in irAEs have not been elucidated.Methods:An osimertinib and ICI-induced irAE mouse model was constructed.Lung micro-CT scans were used to assess the degree of inflammatory infiltration.Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues.Flow cytometry was used to detect the percentages of T cells,NK cells,and macrophages and the expression of EGFR.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum interleukin(IL)-6,alanine transaminase(ALT),ferritin,and tumor necrosis factor(TNF)-αlevels.Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq.Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state.Results:Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6,ALT,and ferritin levels.RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group.Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6,ALT,and ferritin levels in the combination treatment group.Conclusions:An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages,which led to the release of relevant cytokines.展开更多
BACKGROUND Lung squamous cell cancer(LSCC)rarely harbors epidermal growth factor receptor(EGFR)mutations,even much rarer for acquired T790M mutation.Although clinical trials of AURA series illustrated that non-small c...BACKGROUND Lung squamous cell cancer(LSCC)rarely harbors epidermal growth factor receptor(EGFR)mutations,even much rarer for acquired T790M mutation.Although clinical trials of AURA series illustrated that non-small cell lung cancer(NSCLC)with EGFR T790M mutation can benefit from osimertinib,only five LSCC patients were enrolled in total;moreover,the efficacy for LSCC was not shown in the results.Therefore,the response of LSCC to osimertinib is still unclear to date.CASE SUMMARY We report an LSCC case with T790M-related acquired resistance after treatments with first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)and benefited from osimertinib significantly.A 63-year-old Chinese man was diagnosed with stage IV(cT2N2M1b)LSCC harboring an EGFR exon 19-deletion mutation.Following disease progression after gefitinib and multi-line chemotherapy,rebiopsy was conducted.Molecular testing of EGFR by amplification refractory mutation system-polymerase chain reaction detected the exon 19-deletion without T790M mutation.Therefore,the patient was given erlotinib,but progression developed only 3 mo later.Then the frozen re-biopsy tissue was tested by next-generation sequencing(NGS),which detected an EGFR T790M mutation.However,he was very weak with symptoms of dysphagia and cachexia.Fortunately,osimertinib was started,leading to alleviation from the symptoms.Four months later,normal deglutition was restored and partial response was achieved.Finally,the patient achieved an overall survival time period of 29 mo.CONCLUSION Our findings highlight that EGFR T790M mutation may also be an important acquired drug resistance mechanism for LSCC and offer direct evidence of the efficacy of osimertinib in LSCC with T790M mutation.NGS and better preservation conditions may contribute to higher sensitivity of EGFR T790M detection.展开更多
BACKGROUND Patients diagnosed with non-small-cell lung cancer with activated epidermal growth factor receptor mutations are more likely to develop leptomeningeal(LM)metastasis than other types of lung cancers and have...BACKGROUND Patients diagnosed with non-small-cell lung cancer with activated epidermal growth factor receptor mutations are more likely to develop leptomeningeal(LM)metastasis than other types of lung cancers and have a poor prognosis.Early diagnosis and effective treatment of leptomeningeal carcinoma can improve the prognosis.CASE SUMMARY A 55-year-old female with a progressive headache and vomiting for one month was admitted to Peking University First Hospital.She was diagnosed with lung adenocarcinoma with osseous metastasis 10 months prior to admittance.epidermal growth factor receptor(EGFR)mutation was detected by genomic examination,so she was first treated with gefitinib for 10 months before acquiring resistance.Cell-free cerebrospinal fluid(CSF)circulating tumor DNA detection by next-generation sequencing was conducted and indicated the EGFR-Thr790Met mutation,while biopsy and cytology from the patient’s CSF and the first enhanced cranial magnetic resonance imaging(MRI)showed no positive findings.A month later,the enhanced MRI showed linear leptomeningeal enhancement,and the cytology and biochemical examination in CSF remained negative.Therefore,osimertinib(80 mg/d)was initiated as a second-line treatment,resulting in a good response within a month.CONCLUSION This report suggests clinical benefit of osimertinib in LM patients with positive detection of the EGFR-Thr790Met mutation in CSF and proposes that the positive findings of CSF circulating tumor DNA as a liquid biopsy technology based on the detection of cancer-associated gene mutations may appear earlier than the imaging and CSF findings and may thus be helpful for therapy.Moreover,the routine screening of chest CT with the novel coronavirus may provide unexpected benefits。展开更多
BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of cases.Treatment with anti-EGFR antibodies is comm...BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of cases.Treatment with anti-EGFR antibodies is commonplace,but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer.Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis.CASE SUMMARY A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair,scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases.Next generation sequencing revealed a RAS/RAF wild-type,microsatellite stable,PD-L1 negative malignancy.Mutations in TP3 and APC were also identified,as well as EGFR amplification.Cell-free DNA analysis revealed an EGFR T790M mutation.She was unable to tolerate first-line treatment with panitumumab,5-fluorouracil and leucovorin,progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab,and was unable to tolerate third-line treatment with regorafenib.She was started on fourth-line treatment with off-label osimertinib,with clinical response–decrease in size of hepatic metastases and a pericardial effusion.She remained on treatment with osimertinib for seven months.CONCLUSION This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.展开更多
BACKGROUND Osimertinib is the recommended first-line treatment for adult patients with epidermal growth factor receptor(EGFR)mutation positive advanced or metastatic non-small cell lung cancer(NSCLC).However,primary o...BACKGROUND Osimertinib is the recommended first-line treatment for adult patients with epidermal growth factor receptor(EGFR)mutation positive advanced or metastatic non-small cell lung cancer(NSCLC).However,primary or acquired resistance to EGFR-tyrosine kinase inhibitors(EGFR-TKIs)seems inevitable,and when drug-resistance occurs during treatment with osimertinib,the standard of care is to discontinue the TKI.CASE SUMMARY A 57-year-old female patient with lung adenocarcinoma presented with an irritating cough accompanied by chest distress of one month duration.An enhanced head magnetic resonance imaging scan showed brain metastases.An EGFR mutation(exon 21 L858R)was detected in pleural fluid.The patient was treated with oral osimertinib(80 mg once daily)from January 2018 but developed progressive disease on December 2018.She was then successfully treated with rechallenge and tri-challenge with osimertinib(80 mg once daily)by resensitization chemotherapy twice after the occurrence of drug-resistance to osimertinib,and to date has survived for 31 mo.CONCLUSION This case may provide some selective therapeutic options for NSCLC patients with acquired drug-resistance who were previously controlled on osimertinib treatment.展开更多
BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the...BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the two common mutations exon 19 deletion and L858R,which together comprise approximately 85%of EGFR mutations in NSCLC,rare EGFR mutations also exist,including point mutations,deletions,and insertions spanning EGFR exons 18-25.However,the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest.CASE SUMMARY Herein,we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis.The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo.After afatinib failure,the patient received multiple line treatments with chemotherapy.Upon disease progression,the heavily pretreated patient was treated with osimertinib and bevacizumab,and both lung lesion and brain metastases were stable for more than 3 mo.He had an overall survival of 25 mo.CONCLUSION Our case revealed that both afatinib and the osimertinib+bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833FL861Q compound mutation.The results provide more therapeutic options for patients with rare compound mutations.展开更多
<span style="font-family:Verdana;">The present work encompasses identification and characterization of major degradation product (DP) of OSM observed in base hydrolytic stress study. The separation of ...<span style="font-family:Verdana;">The present work encompasses identification and characterization of major degradation product (DP) of OSM observed in base hydrolytic stress study. The separation of DP was carried out on a non-polar stationary phase by using high-performance liquid chromatography system (HPLC). Using waters X-bridge (250 mm × 4.6 mm, 5 μm) C18 column with gradient elution program. For the characterization study, stress samples were subjected to HPLC and UPLC-QTOF-MS/MS and based on mass fragmentation pattern</span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">,</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> plausible structure was deduced. Further</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">,</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> the DP was isolated using semi-prepara</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">- </span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">tive liquid chromatography and concentrated the fractions using lyophiliza</span><span style="font-family:Verdana;">tion. The isolated DP was subjected to extensive 1D (1H, 13C, and</span><span style="font-family:Verdana;"> DEPT-135) and 2D (COSY, HSQC and HMBC) nuclear magnetic resonance (NMR) studies to authenticate the structure. The impurity was unambiguously named as N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-metho</span></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">-</span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">xy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-3-methoxy</span><span style="font-family:Verdana;">propanamide.</span></span></span></span><span><span><span style="font-family:;" "=""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">Add</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">- </span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">itionally, the </span><i><span style="font-family:Verdana;">In-Silico</span></i><span style="font-family:Verdana;"> structure activity relation (QSAR) assessed through sta</span></span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">tistical based software’s DEREK Nexus</span><sup><span style="font-family:Verdana;">TM</span></sup><span style="font-family:Verdana;">, and MultiCASE, Case Ultra</span><sup><span style="font-family:Verdana;">TM</span></sup></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> widely accepted and respected software’s for DP and OSM</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">.</span></span></span>展开更多
In the era of precision oncology,molecular profiling of tumor biopsy or plasma(also known as liquid biopsy)derived from patients with cancer is pivotal in guiding treatment selection.Liquid biopsy allows for the ident...In the era of precision oncology,molecular profiling of tumor biopsy or plasma(also known as liquid biopsy)derived from patients with cancer is pivotal in guiding treatment selection.Liquid biopsy allows for the identification of druggable biomarkers,facilitating optimal cancer care management.1 Non-small cell lung cancer(NSCLC)is at the forefront because of the diverse genetic biomarkers currently approved for guiding targeted therapies.Mesenchymal epithelial transition(MET)is a receptor tyrosine kinase with pleiotropic functions,such as initiating and sustaining neoplastic transformation,driving cancer clonal evolution,and progression toward metastasis after treatment initiation and under therapeutic pressure.2 Exon 14 skipping(METex14skipping)and amplification(METamp)are two important MET dysregulations in NSCLC with distinct oncogenic roles.The concurrent presence of these two MET alterations in patients with NSCLC has rarely been reported,and knowledge of their collective impact on patient response to MET inhibitors such as capmatinib remains elusive.In this paper,we report the case of a 60-year-old woman diagnosed with lung adenocarcinoma and brain metastasis who progressed on first-line(1L)osimertinib treatment with new liver metastasis,along with the outcomes of subsequent testing and treatment management.展开更多
Aims:The study aimed to evaluate the effectiveness and adverse events of tyrosine kinase inhibitors(TKIs)in the first-line treatment of advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(E...Aims:The study aimed to evaluate the effectiveness and adverse events of tyrosine kinase inhibitors(TKIs)in the first-line treatment of advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations.Methods:A retrospective study on advanced NSCLC patients with EGFR mutations treated with TKIs as a first-line therapy at Nghe An Oncology Hospital,Vietnam between January 2017 and August 2023.The primary endpoints included objective response rate,progression-free survival,and tolerability.The secondary endpoint was overall survival.Results:A total of 211 patients received first-line treatment with Erlotinib(n=74),Gefitinib(n=85),Afatinib(n=34)or Osimertinib(n=18).The overall response rate was 76.7%,with Osimertinib at 83.4%,Afatinib at 73.6%,Erlotinib at 77.1%,and Gefitinib at 76.5%.The median progression-free survival in the Gefitinib group was 12.2 months(95%CI:11.1-13.2),13.4 months(95%CI:10.6-16.2)in the Erlotinib group,18.4 months(95%CI:10.1-26.8)in the Afatinib group and 25.3 months in the Osimertinib group(p=0.001).The median overall survival was 21.8 months(95%Cl:15.0-28.4)in the Gefitinib group,30 months(95%Cl:19.1-40.9)in the Erlotinib group(p=0.154).Most drug-related adverse events were grade 1 or 2.Diarrhea was the most frequent adverse event in the Afatinib group at 44.1%;rash was most common in the Erlotinib group at 60.8%;paronychia(31.8%),and interstitial lung disease(3.5%)were most frequent in the Gefitinib group.Conclusion:The TKIs as first-line therapies for advanced NSCLC patients with EGFR mutated are highly effective,prolong survival,and are well tolerated.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82172728,82370096).
文摘In the present study,we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition(EMT)and angiogenesis.In a clinical case,anlotinib reversed osimertinib resistance in non-small cell lung cancer(NSCLC).Therefore,we performed immunohistochemical analyses on tumor tissues from three NSCLC patients with osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A(VEGFA)before and after the development of osimertinib resistance.The results revealed the downregulation of E-cadherin,coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance,compared with those in tissues from patients before receiving osimertinib.Subsequently,we established osimertinib-resistant(Osi-R)cell lines and found that the Osi-R cells acquired EMT features.Next,we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT.The expression levels of VEGFA and tube formation were analyzed in the combination group in vitro.Finally,we determined the reversal of osimertinib resistance by the combination of osimertinib and anlotinib in vivo using 20 nude mice.The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of Osi-R cells,inhibited tumor growth,exerted antitumor activity,and ultimately reversed osimertinib resistance in mice.The co-administration of osimertinib and anlotinib demonstrated synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients,ultimately reversing osimertinib resistance.
基金Supported by Guangxi Guilin Science and Technology Fund,No.20190218-7-6.
文摘BACKGROUND Most non-small cell lung cancer patients have epidermal growth factor receptor(EGFR)activating mutations,such as exon 19 deletion and exon 21 replacement mutations.Osimertinib is a third-generation EGFR-tyrosine kinase inhibitors ap-proved for the treatment of lung cancer patients carrying EGFR activating mu-tations.Osimertinib-induced interstitial lung disease(ILD)is a rare and poten-tially fatal pulmonary toxic manifestation of drug therapy.At present,there is no international consensus on the risks and treatment of the osimertinib-induced ILD.CASE SUMMARY We report a case of a 56-year-old woman who was diagnosed with lung adenocar-cinoma with lung hilum,mediastinal lymph nodes and brain metastases(T4N3-M1c stage IVB).The patient received targeted treatment with osimertinib after radiotherapy and chemotherapy.But she developed ILD after osimertinib treat-ment.Following active symptomatic treatment and hormone treatment,the lung injury alleviated.The patient was retreated with furmonertinib combined with prednisone and did not experience ILD again.So far,she has survived for 14 months without disease progression.CONCLUSION Retreatment with furmonertinib under prednisone could be considered as an effective therapeutic option after risk-benefit assessment for EGFR-mutant lung adenocarcinoma patients.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82172653 and 82472728)the Key Project of Developmental Biology and Breeding from Hunan Province(Grant No.2022XKQ0205)+1 种基金the Research Team for Reproduction Health and Translational Medicine of Hunan Normal University(Grant No.2023JC101)the Natural Science Foundation of Hunan Province(Grant No.2025JJ80150).
文摘Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.
基金funded by grants from the National Natural Science Foundation of China(Grant Nos.82003288,U20A20375,82372779,and 82103001)Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-009A).
文摘Objective:The combination of epithelial growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)and immune checkpoint inhibitors(ICIs)leads to an increased incidence of severe immune-related adverse events(irAEs).However,the mechanisms underlying macrophages in irAEs have not been elucidated.Methods:An osimertinib and ICI-induced irAE mouse model was constructed.Lung micro-CT scans were used to assess the degree of inflammatory infiltration.Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues.Flow cytometry was used to detect the percentages of T cells,NK cells,and macrophages and the expression of EGFR.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum interleukin(IL)-6,alanine transaminase(ALT),ferritin,and tumor necrosis factor(TNF)-αlevels.Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq.Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state.Results:Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6,ALT,and ferritin levels.RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group.Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6,ALT,and ferritin levels in the combination treatment group.Conclusions:An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages,which led to the release of relevant cytokines.
基金Supported by the National Natural Science Foundation of China,No.81402561
文摘BACKGROUND Lung squamous cell cancer(LSCC)rarely harbors epidermal growth factor receptor(EGFR)mutations,even much rarer for acquired T790M mutation.Although clinical trials of AURA series illustrated that non-small cell lung cancer(NSCLC)with EGFR T790M mutation can benefit from osimertinib,only five LSCC patients were enrolled in total;moreover,the efficacy for LSCC was not shown in the results.Therefore,the response of LSCC to osimertinib is still unclear to date.CASE SUMMARY We report an LSCC case with T790M-related acquired resistance after treatments with first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)and benefited from osimertinib significantly.A 63-year-old Chinese man was diagnosed with stage IV(cT2N2M1b)LSCC harboring an EGFR exon 19-deletion mutation.Following disease progression after gefitinib and multi-line chemotherapy,rebiopsy was conducted.Molecular testing of EGFR by amplification refractory mutation system-polymerase chain reaction detected the exon 19-deletion without T790M mutation.Therefore,the patient was given erlotinib,but progression developed only 3 mo later.Then the frozen re-biopsy tissue was tested by next-generation sequencing(NGS),which detected an EGFR T790M mutation.However,he was very weak with symptoms of dysphagia and cachexia.Fortunately,osimertinib was started,leading to alleviation from the symptoms.Four months later,normal deglutition was restored and partial response was achieved.Finally,the patient achieved an overall survival time period of 29 mo.CONCLUSION Our findings highlight that EGFR T790M mutation may also be an important acquired drug resistance mechanism for LSCC and offer direct evidence of the efficacy of osimertinib in LSCC with T790M mutation.NGS and better preservation conditions may contribute to higher sensitivity of EGFR T790M detection.
文摘BACKGROUND Patients diagnosed with non-small-cell lung cancer with activated epidermal growth factor receptor mutations are more likely to develop leptomeningeal(LM)metastasis than other types of lung cancers and have a poor prognosis.Early diagnosis and effective treatment of leptomeningeal carcinoma can improve the prognosis.CASE SUMMARY A 55-year-old female with a progressive headache and vomiting for one month was admitted to Peking University First Hospital.She was diagnosed with lung adenocarcinoma with osseous metastasis 10 months prior to admittance.epidermal growth factor receptor(EGFR)mutation was detected by genomic examination,so she was first treated with gefitinib for 10 months before acquiring resistance.Cell-free cerebrospinal fluid(CSF)circulating tumor DNA detection by next-generation sequencing was conducted and indicated the EGFR-Thr790Met mutation,while biopsy and cytology from the patient’s CSF and the first enhanced cranial magnetic resonance imaging(MRI)showed no positive findings.A month later,the enhanced MRI showed linear leptomeningeal enhancement,and the cytology and biochemical examination in CSF remained negative.Therefore,osimertinib(80 mg/d)was initiated as a second-line treatment,resulting in a good response within a month.CONCLUSION This report suggests clinical benefit of osimertinib in LM patients with positive detection of the EGFR-Thr790Met mutation in CSF and proposes that the positive findings of CSF circulating tumor DNA as a liquid biopsy technology based on the detection of cancer-associated gene mutations may appear earlier than the imaging and CSF findings and may thus be helpful for therapy.Moreover,the routine screening of chest CT with the novel coronavirus may provide unexpected benefits。
文摘BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of cases.Treatment with anti-EGFR antibodies is commonplace,but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer.Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis.CASE SUMMARY A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair,scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases.Next generation sequencing revealed a RAS/RAF wild-type,microsatellite stable,PD-L1 negative malignancy.Mutations in TP3 and APC were also identified,as well as EGFR amplification.Cell-free DNA analysis revealed an EGFR T790M mutation.She was unable to tolerate first-line treatment with panitumumab,5-fluorouracil and leucovorin,progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab,and was unable to tolerate third-line treatment with regorafenib.She was started on fourth-line treatment with off-label osimertinib,with clinical response–decrease in size of hepatic metastases and a pericardial effusion.She remained on treatment with osimertinib for seven months.CONCLUSION This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.
基金The Natural Science Foundation Project of Anhui Province,No.1808085MH267Key Research and Development Project of Anhui Province,No.202004a07020020.
文摘BACKGROUND Osimertinib is the recommended first-line treatment for adult patients with epidermal growth factor receptor(EGFR)mutation positive advanced or metastatic non-small cell lung cancer(NSCLC).However,primary or acquired resistance to EGFR-tyrosine kinase inhibitors(EGFR-TKIs)seems inevitable,and when drug-resistance occurs during treatment with osimertinib,the standard of care is to discontinue the TKI.CASE SUMMARY A 57-year-old female patient with lung adenocarcinoma presented with an irritating cough accompanied by chest distress of one month duration.An enhanced head magnetic resonance imaging scan showed brain metastases.An EGFR mutation(exon 21 L858R)was detected in pleural fluid.The patient was treated with oral osimertinib(80 mg once daily)from January 2018 but developed progressive disease on December 2018.She was then successfully treated with rechallenge and tri-challenge with osimertinib(80 mg once daily)by resensitization chemotherapy twice after the occurrence of drug-resistance to osimertinib,and to date has survived for 31 mo.CONCLUSION This case may provide some selective therapeutic options for NSCLC patients with acquired drug-resistance who were previously controlled on osimertinib treatment.
文摘BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the two common mutations exon 19 deletion and L858R,which together comprise approximately 85%of EGFR mutations in NSCLC,rare EGFR mutations also exist,including point mutations,deletions,and insertions spanning EGFR exons 18-25.However,the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest.CASE SUMMARY Herein,we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis.The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo.After afatinib failure,the patient received multiple line treatments with chemotherapy.Upon disease progression,the heavily pretreated patient was treated with osimertinib and bevacizumab,and both lung lesion and brain metastases were stable for more than 3 mo.He had an overall survival of 25 mo.CONCLUSION Our case revealed that both afatinib and the osimertinib+bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833FL861Q compound mutation.The results provide more therapeutic options for patients with rare compound mutations.
文摘<span style="font-family:Verdana;">The present work encompasses identification and characterization of major degradation product (DP) of OSM observed in base hydrolytic stress study. The separation of DP was carried out on a non-polar stationary phase by using high-performance liquid chromatography system (HPLC). Using waters X-bridge (250 mm × 4.6 mm, 5 μm) C18 column with gradient elution program. For the characterization study, stress samples were subjected to HPLC and UPLC-QTOF-MS/MS and based on mass fragmentation pattern</span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">,</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> plausible structure was deduced. Further</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">,</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> the DP was isolated using semi-prepara</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">- </span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">tive liquid chromatography and concentrated the fractions using lyophiliza</span><span style="font-family:Verdana;">tion. The isolated DP was subjected to extensive 1D (1H, 13C, and</span><span style="font-family:Verdana;"> DEPT-135) and 2D (COSY, HSQC and HMBC) nuclear magnetic resonance (NMR) studies to authenticate the structure. The impurity was unambiguously named as N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-metho</span></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">-</span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">xy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-3-methoxy</span><span style="font-family:Verdana;">propanamide.</span></span></span></span><span><span><span style="font-family:;" "=""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">Add</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">- </span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">itionally, the </span><i><span style="font-family:Verdana;">In-Silico</span></i><span style="font-family:Verdana;"> structure activity relation (QSAR) assessed through sta</span></span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">tistical based software’s DEREK Nexus</span><sup><span style="font-family:Verdana;">TM</span></sup><span style="font-family:Verdana;">, and MultiCASE, Case Ultra</span><sup><span style="font-family:Verdana;">TM</span></sup></span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> widely accepted and respected software’s for DP and OSM</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">.</span></span></span>
文摘In the era of precision oncology,molecular profiling of tumor biopsy or plasma(also known as liquid biopsy)derived from patients with cancer is pivotal in guiding treatment selection.Liquid biopsy allows for the identification of druggable biomarkers,facilitating optimal cancer care management.1 Non-small cell lung cancer(NSCLC)is at the forefront because of the diverse genetic biomarkers currently approved for guiding targeted therapies.Mesenchymal epithelial transition(MET)is a receptor tyrosine kinase with pleiotropic functions,such as initiating and sustaining neoplastic transformation,driving cancer clonal evolution,and progression toward metastasis after treatment initiation and under therapeutic pressure.2 Exon 14 skipping(METex14skipping)and amplification(METamp)are two important MET dysregulations in NSCLC with distinct oncogenic roles.The concurrent presence of these two MET alterations in patients with NSCLC has rarely been reported,and knowledge of their collective impact on patient response to MET inhibitors such as capmatinib remains elusive.In this paper,we report the case of a 60-year-old woman diagnosed with lung adenocarcinoma and brain metastasis who progressed on first-line(1L)osimertinib treatment with new liver metastasis,along with the outcomes of subsequent testing and treatment management.
文摘Aims:The study aimed to evaluate the effectiveness and adverse events of tyrosine kinase inhibitors(TKIs)in the first-line treatment of advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations.Methods:A retrospective study on advanced NSCLC patients with EGFR mutations treated with TKIs as a first-line therapy at Nghe An Oncology Hospital,Vietnam between January 2017 and August 2023.The primary endpoints included objective response rate,progression-free survival,and tolerability.The secondary endpoint was overall survival.Results:A total of 211 patients received first-line treatment with Erlotinib(n=74),Gefitinib(n=85),Afatinib(n=34)or Osimertinib(n=18).The overall response rate was 76.7%,with Osimertinib at 83.4%,Afatinib at 73.6%,Erlotinib at 77.1%,and Gefitinib at 76.5%.The median progression-free survival in the Gefitinib group was 12.2 months(95%CI:11.1-13.2),13.4 months(95%CI:10.6-16.2)in the Erlotinib group,18.4 months(95%CI:10.1-26.8)in the Afatinib group and 25.3 months in the Osimertinib group(p=0.001).The median overall survival was 21.8 months(95%Cl:15.0-28.4)in the Gefitinib group,30 months(95%Cl:19.1-40.9)in the Erlotinib group(p=0.154).Most drug-related adverse events were grade 1 or 2.Diarrhea was the most frequent adverse event in the Afatinib group at 44.1%;rash was most common in the Erlotinib group at 60.8%;paronychia(31.8%),and interstitial lung disease(3.5%)were most frequent in the Gefitinib group.Conclusion:The TKIs as first-line therapies for advanced NSCLC patients with EGFR mutated are highly effective,prolong survival,and are well tolerated.
