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Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells

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Chinese Chemical Letters 2024年第2期35卷 436-440页

作者： Guizhen Zhu Yaoyao Zhao Wenmei Zhang Yuanyuan Wu Yuanxing Liu Guangsheng Guo Xiayan Wang Zhihong Liu Center of Excellence for Environmental Safety and Biological Effects Beijing Key Laboratory for Green Catalysis and SeparationDepartment of ChemistryBeijing University of TechnologyBeijing 100124China Minzu University of China Beijing 100081China Key Laboratory for the Synthesis and Application of Organic Functional Molecules College of Health Science and EngineeringHubei UniversityWuhan 430062China

Patients with epidermal growth factor receptor(EGFR)wild-type non-small cell lung cancer(NSCLC)often show primary resistance to gefitinib therapy.It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors.Herein,we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry(sDMH-scMS)by integrating living-cell electrolaunching ionization MS(ILCEI-MS)and high-performance liquid chromatography-MS(HPLC-MS)analysis,and the primary resistance of NSCLC cells to gefitinib was studied using this platform.The ILCEI-MS analysis showed that approximately 11.9%of NSCLC single cells contained the gefitinib metabolite M11;HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells.The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells,and the intensity of gefitinib metabolites was significantly higher than in PC9 cells,suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism.Moreover,the combination of gefitinib and the drug-metabolizing enzyme inhibitorα-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells.Overall,the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.

关键词： Single-cell mass spectrometry Drug metabolism Non-small cell lung cancer gefitinib Primary resistance

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gefitinib improves severe bronchorrhea and prolongs the survival of a patient with lung invasive mucinous adenocarcinoma:A case report

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World Journal of Clinical Cases 2023年第2期11卷 441-448页

作者： Guo-Chun Ou Wen Luo Wei-Shan Zhang Shu-Hong Wang Jie Zhao Hong-Mei Zhao Rong Qiu Department of Respiratory and Critical Care Medicine Suining Central HospitalSuining 629000Sichuan ProvinceChina Department of Pathology Suining Central HospitalSuining 629000Sichuan ProvinceChina

BACKGROUND Lung invasive mucinous adenocarcinoma(LIMA),formerly referred to as mucinous bronchioloalveolar carcinoma,is a rare disease that usually presents as bilateral lung infiltration,is unsuitable for surgery and radiotherapy,and shows poor response to conventional chemotherapy.CASE SUMMARY We report a 56-year-old Chinese man with a history of smoking and epidermal growth factor receptor mutation-positivity who was initially misdiagnosed as severe pneumonia,but was ultimately diagnosed as a case of invasive mucinous adenocarcinoma of the lung by computed tomography-guided percutaneous lung biopsy.Bronchorrhea and dyspnea were improved within 24 h after initiation of gefitinib therapy and the radiographic signs of bilateral lung consolidation showed visible improvement within 30 d.After more than 11 months of treatment,there is no evidence of recurrence or severe adverse events.CONCLUSION Although the precise mechanism of the antitumor effects of gefitinib are not clear,our experience indicates an important role of the drug in LIMA and provides a reference for the diagnosis and treatment of this disease.

关键词： gefitinib Epidermal growth factor receptor Lung cancer Bronchorrhea Lung invasive mucinous adenocarcinoma Case report

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FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3639-3649页

作者： Shaoxing Guan Xi Chen Youhao Chen Guohui Wan Qibiao Su Heng Liang Yunpeng Yang Wenfeng Fang Yan Huang Hongyun Zhao Wei Zhuang Shu Liu Fei Wang Wei Feng Xiaoxu Zhang Min Huang Xueding Wang Li Zhang Laboratory of Drug Metabolism and Pharmacokinetics School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510060China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China College of Health Science Guangdong Pharmaceutical UniversityGuangzhou 510006China Sun Yat-sen Memorial Hospital Sun Yat-sen UniversityGuangzhou 510080China Ersha Department of Pharmacy the Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510105China

Hepatotoxicity is a common side effect for patients treated with gefitinib,but the related pathogenesis is unclear and lacks effective predictor and management strategies.A multi-omics approach integrating pharmacometabolomics,pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution.Here,we found that patients with rs4946935 AA,located in Forkhead Box O3(FOXO3)which is a well-known autophagic regulator,had a higher risk of hepatotoxicity than those with the GA or GG variant(OR=18.020,95%CI=2.473 to 459.1784,P=0.018)in a gefitinib-concentration dependent pattern.Furthermore,functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity,increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury.In contrast,erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3.This study reveals that FOXO3 mutation,leading to autophagic imbalance,plays important role in gefitinib-induced hepatotoxicity,especially for patients with high concentration of gefitinib.In conclusion,FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.

关键词： gefitinib Hepatotoxicity Pharmacometabolomic Pharmacokinetics Pharmacogenomics FOXO3 Autophagy

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The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer

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Cancer Biology & Medicine 2022年第8期19卷 1172-1192页

作者： Ting He Yinglei Gao Yanfen Fang Yangming Zhang Shuwei Zhang Fajun Nan Jian Ding Yi Chen Division of Anti-Tumor Pharmacology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Drug Research the National Center for Drug ScreeningShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Objective:The novel compound GCJ-490A has been discovered as a pan-histone deacetylase(HDAC)inhibitor that exerts potent inhibitory activity against HDAC1,HDAC3,and HDAC6.Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue,we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer(NSCLC)in vitro and in vivo in this study.Methods:The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation,apoptosis,and colony formation assays.NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo.Western blot assays,luciferase reporter assays,chromatin immunoprecipitation assays,quantitative real time-PCR,immunohistochemistry,and transcription factor activity assays were used to elucidate possible mechanisms.Results:GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo.Interestingly,inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKαpromoter and enhanced IKKαtranscription,thus decreasing c-Met.Moreover,this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib.Conclusions:These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.

关键词： HDAC inhibitor c-Met IKKα NSCLC gefitinib

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gefitinib facilitates PINK1/Parkin-mediated mitophagy by enhancing mitochondrial recruitment of OPTN

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Fundamental Research 2022年第5期2卷 807-816页

作者： Ningning Li Shan Sun Guoqiang Ma Hongyu Hou Qilian Ma Li Zhang Zengli Zhang Hongfeng Wang Zheng Ying Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhouJiangsu 215123China Department of Respiratory and Critical Care Medicine The Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu 215004China Key Laboratory of Nuclear Medicine Ministry of HealthJiangsu Key Laboratory of Molecular Nuclear MedicineJiangsu Institute of Nuclear MedicineWuxiJiangsu 214063China

gefitinib,a well-known epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor for the targeted therapy of lung cancer,induces autophagy in association with drug resistance.However,it remains unclear whether gefitinib treatment can affect the selective form of autophagy(i.e.,mitophagy)and be beneficial for the treatment of human diseases with decreased autophagy,such as neurodegenerative diseases.Here,we show that gefitinib treatment promotes PINK1/Parkin-mediated mitophagy in both nonneuronal and neuronal cells,and this effect is independent of EGFR.Moreover,we found that gefitinib treatment increases the recruitment of the autophagy receptor optineurin(OPTN)to damaged mitochondria,which is a downstream signaling event in PINK1/Parkin-mediated mitophagy.In addition,gefitinib treatment significantly alleviated neuronal damage in TBK1-deficient neurons,resulting in impeded mitophagy.In conclusion,our study suggests that gefitinib promotes PINK1/Parkin-mediated mitophagy via OPTN and may be beneficial for the treatment of neurodegenerative diseases that are associated with defective mitophagy.

关键词： gefitinib Autophagy Mitophagy Parkin OPTN

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gefitinib attenuates murine pulmonary fibrosis induced by bleomycin

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Chinese Medical Journal 2010年第16期123卷 2259-2264页

作者： WANG Ping TIAN Qing LIANG Zhi-xin YANG Zhen XU Shu-feng SUN Ji-ping CHEN Liang-an Department of Respiratory Medicine Chinese People's Liberation Army General Hospital Beijing 100853 China Department of Respiratory Medicine the First Hospital of Qinhuangdao Qinhuangdao Hebei 066000 China

Background gefitinib, an inhibitor of epidermal growth factor receptor （EGFR） tyrosine kinase, is an effective treatment for epithelial tumors, including non-small cell lung cancer （NSCLC）, and is generally well tolerated.However, some clinical trials revealed that gefitinib exposure caused lung fibrosis, a severe adverse reaction.This study investigated the effect of gefitinib on lung fibrosis in mice.Methods We generated a mouse model of lung fibrosis induced by bleomycin to investigate the fibrotic effect of gefitinib.C57BL/6 mice were injected intratracheally with bleomycin or saline, with intragastric administration of gefitinib or saline.Lung tissues were harvested on day 14 or 21 for histology and genetic analysis.Results The histological results showed that bleomycin successfully induced lung fibrosis in mice, and gefitinib prevented lung fibrosis and suppressed the proliferation of S100A4-positive fibroblast cells.In addition, Western blotting analysis revealed that gefitinib decreased the expression of phosphorylated EGFR （p-EGFR）.Furthermore, quantitative real-time PCR （qRT-PCR） demonstrated that gefitinib inhibited the accumulation of collagens Ⅰ and Ⅲ.Conclusions These results reveal that gefitinib reduces pulmonary fibrosis induced by bleomycin in mice and suggest that administration of small molecule EGFR tyrosine kinase inhibitors has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that targeting tyrosine kinase receptors might be useful for the treatment of pulmonary fibrosis in humans.

关键词： gefitinib epidermal growth factor tyrosine kinase inhibitor fibroblasts idiopathic pulmonary fibrosis

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gefitinib-induced disseminated intravascular coagulation in a patient with non-small cell lung cancer

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Chinese Medical Journal 2010年第4期123卷 505-506页

作者： YUAN Guang-jin KE Qin-hua XU Xi-ming YANG Ji-yuan SU Xiao-yan Cancer Center 82nd Hospital of the Chinese People's Liberation Army Hnai'an Jiangsn 223001 China Deprtment of Oncology First People's Hospital of Jingzhou Jingzhou Hubei 434000 China Cancer Center Renmin Hospital of Wuhan University Wuhan Hubei 430060 China

In February 2005, gefitinib （Iressa）, a small-molecular .epidermal growth factor receptor and tyrosine kinaseinhibitor, was approved in China as an anticancer agent for patients with advanced （local or metastatic） non-small cell lung cancer （NSCLC）, who failed prior chemotherapy. The common adverse events of the drug include acne-like skin rash, paronychia, pruritus, diarrhea, nausea/vomiting, anorexia, hepatitis, and hyperbilirubinemia.1 However, these adverse events are generally mild in severity and reversible on cessation of the treatment. Therefore, gefitinib has been regarded as a relatively safe agent,

关键词： gefitinib non-small cell lung cancer disseminated intravascular coagulation adverse event

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EFFICACY AND SAFETY OF gefitinib AS MONOTHERAPY FOR CHINESE PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER

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Chinese Medical Journal 2006年第1期119卷 63-68页

作者： WANG Meng-zhao LI Long-yun WANG Shu-lan ZHANG Xiao-tong ZHONG Wei ZHANG Li Department of Respiratory Diseases Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy of Medical Sciences Beijing 100730 China

Platinum-based chemotherapy can improve the survival and quality of life of patients with locally advanced and metastatic lung cancer. Second-line docetaxel monotherapy can improve overall survival following the failure of first line chemotherapy. However, many limiting factors such as poor performance status, advanced age, adverse effects of chemotherapy and reluctance to receive cytotoxic chemotherapeutic agents render patients unable to accept chemotherapy.

关键词： non-small cell lung cancer gefitinib treatment

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Recurrence patterns of advanced non-small cell lung cancer treated with gefitinib

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Chinese Medical Journal 2013年第12期126卷 2235-2241页

作者： CHEN Min-jiang ZHONG Wei ZHANG Li ZHAO Jing LI Long-yun WANG Meng-zhao Department of Respiratory Medicine Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100730 China

Background gefitinib is widely used in the treatment of advanced non-small cell lung cancer （NSCLC）.However,only a small number of reports have described initial failure sites in patients treated with gefitinib.The aim of this study was to investigate survival,recurrence sites,and treatment after recurrence in these patients.Methods A retrospective review was conducted of all patients with stage Ⅲ/Ⅳ NSCLC treated with gefitinib in Peking Union Medical College Hospital from October 2002 to September 2011.Patient characteristics,initial failure sites,associated clinical factors,and subsequent therapy were included in the analysis of prognostic factors.Results A total of 316 patients were identified The median progress free survival （PFS） and overall survival （OS） times were 238 days and 468 days,respectively.The median survival time after progression was 145 days.The sites of initial failure were lung （62.34%）,bone （17.72%）,central nerve system （CNS,16.14%）,liver （9.49%）,and others （7.19%）.Patients with single-site progression or multi-site progression were 81.01% and 18.99%,respectively.Progression-free survival time was associated with lung and bone failure.Additionally,the median survival time after progression was lower in patients with multi-site progression and liver progression.Other initial failure sites displayed no relationship with survival,including CNS failure.Subsequent therapy may affect survival after progression.In patients receiving continuous epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TKI） therapy,chemotherapy,radiotherapy,and retreatment with EGFR-TKIs,survival time after progression was prolonged compared with the best supportive care.Conclusions Our data suggest that patients receiving gefltinib should be closely monitored regarding lung metastasis during follow-up.Liver metastases and multi-site progression were poor prognostic factors.After failure with gefltinib,patients may benefit from radiotherapy,chemotherapy,continuous EGFR-TKI therapy and re-treatment with EGFR-T

关键词： non-small cell lung cancer recurrence gefitinib

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Chemotherapy with or without gefitinib in patients with advanced non-small-cell lung cancer： a meta-analysis of 6844 patients

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Chinese Medical Journal 2013年第17期126卷 3348-3355页

作者： ZHOU Hang ZENG Chao WANG Li-yang XIE Hua ZHOU Jin DIAO Peng YAO Wen-xiu ZHAO Xin WEI Yang Department of Chemotherapy Sichuan Cancer Hospital Chengdu Sichuan 610041 China Department of Gastroenterology Third People's Hospital of Chengdu Chengdu Sichuan 610031 China

Background gefitinib is widely used in patients with advanced non-small-cell lung cancer （NSCLC）, in whom chemotherapy had failed. Previous trials reported inconsistent findings regarding the efficacy of gefitinib on overall survival （OS） and progression free survival （PFS）. This study was to evaluate the effects of chemotherapy plus gefitinib versus chemotherapy alone on survival of patients with NSCLC. Methods We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings for relevant literature. Randomized controlled trials （RCTs） comparing chemotherapy with and without gefitinib in the treatment of patients with advanced NSCLC were included in our analysis. The primary endpoints were OS and PFS. Results Of 182 relevant studies, 12 were included in the final analysis, which consisted of 6844 patients with NSCLC. Overall, we noted that gefitinib therapy had an 8% improvement in the OS as compared to the gefitinib-free therapy, but this difference was not statistically significant （HR, 0.92; 95% CI： 0.85-1.00; P=0.051）. Furthermore, gefitinib therapy had significantly longer PFS compared to gefitinib-free therapy （HR, 0.72; 95% CI 0.60-0.87, P=0.001）. Patients receiving gefitinib therapy also had a more frequent objective response rate （ORR） than the control arm （OR, 2.51; 95% CI, 1.67- 3.78, P 〈0.001）. Rashes, diarrhea, dry skin, pruritus, paronychia, and abnormal hepatic function were more frequent in the gefitinib therapy group. Conclusions Treatment with gefitinib had a clear effect on PFS and ORR, and it might contribute considerably to the OS. Furthermore, there was some evidence of benefit for gefitinib therapy among patients with adenocarcinoma.

关键词： non-small-cell-lung cancer gefitinib meta-analysis

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