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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

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

gefitinib plus Fuzheng Kang'ai Formula(扶正抗癌方) in Patients with Advanced Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation:A Randomized Controlled Trial

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Chinese Journal of Integrative Medicine 2018年第10期24卷 734-740页

作者： YANG Xiao-bing CHAI Xiao-shu WU Wan-yin LONG Shun-qin DENG Hong PAN Zong-qi HE Wen-feng ZHOU Yu-shu LIAO Gui-ya XIAO Shu-jing Department of Oncology Guangdong Provincial Hospital of Traditional Chinese Medicine

Objective： To evaluate the effect of Fuzheng Kang＇ai Formula （扶正抗癌方, FZKA） plus gefitinib in patients with advanced non-small cell lung cancer with epidermal growth factor receptor （EGFR） mutations. Methods： A randomized controlled trial was conducted from 2009 to 2012 in South China. Seventy chemotherapynaive patients diagnosed with stage ⅢB/Ⅳ non-small cell lung cancer with EGFR mutations were randomly assigned to GF group [gefitinib （250 mg/day orally） plus FZKA （250 mL, twice per day, orally）; 35 cases] or G group （gefitinib 250 mg/day orally; 35 cases） according to the random number table and received treatment until progression of the disease, or development of unacceptable toxicities. The primary endpoint [progression-free survival （PFS）] and secondary endpoints [median survival time （MST）, objective response rate （ORR）, disease control rate （DCR） and safety] were observed. Results： No patient was excluded after randomization. GF group had significantly longer PFS and MST compared with the G group, with median PFS of 12.5 months （95% CI 3.30-21.69） vs. 8.4 months （95% CI 6.30-10.50; log-rank P〈0.01）, MST of 21.5 months （95% CI 17.28-25.73） vs. 18.3 months （95% CI 17.97-18.63; log-rank P〈0.01）. ORR and DCR in GF group and G group were 65.7% vs. 57.1%, 94.3% vs. 80.0%, respectively （P〉0.05）. The most common toxic effects in the GF group and G group were rash or acne （42.8% vs. 57.1%, P〉0.05）, diarrhea （11.5% vs. 31.4%, P〈0.05）, and stomatitis （2.9% vs. 8.7%, P〉0.05）. Conclusion： Patients with advanced non-small cell lung cancer selected by EGFR mutations have longer PFS, MST with less toxicity treated with gefitinib plus FZKA than gefitinib alone.

关键词： non-small cell lung cancer gefitinib Chinese medicine combination therapy sensitizing effect Fuzheng Kang＇ai Formula randomized controlled trial

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

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

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

Alterations of gefitinib Pharmacokinetics by Co-administration of Herbal Medications in Rats

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Chinese Journal of Integrative Medicine 2018年第6期24卷 460-466页

作者： Kwon-Yeon Weon Min Gi Kim Soyoung Shin Tae Hwan Kim Sang Hoon Joo Eunsook Ma Seok Won Jeong Sun Dong Yoo Yu Seok Youn Beom Soo Shin College of Pharmacy Catholic University of Daegu School of Pharmacy Sungkyunkwan University College of Pharmacy Wonkwang University

Objective： To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib （Iressae） and the oriental medications Guipi Decoction （归脾汤, GPD, Guibi-tang in Korean） and Bawu Decoction （八物汤, BWD, Palmul-tang in Korean）. Methods： Methylceliulose （MC, control）, GPD （1,200 mg/kg）, or BWD （6,000 mg/kg） was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib （10 mg/kg） was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefltinib （10 mg/kg） was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis. Results： gefitinib was rapidly absorbed and showed a mono- exponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration （Crux, P〈0.05） and area under the curve （P〈0.05）, and a delayed time to reach Cmax （Tmax, P〈0.01） were observed in both single- and multiple- dose BWD-pretreated rats compared with the control rats. Conclusions： BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.

关键词： herb-drug interaction pharmacokinetics gefitinib Guipi Decoction Bawu Decoction

gefitinib酸性改造增敏其对非小细胞肺癌疗效

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Gefitinib酸性改造增敏其对非小细胞肺癌疗效

作者：胡诗曼浙江大学

学位级别：硕士

背景:全世界的统计数据表明,肺癌仍然是导致癌症发生率和癌症死亡率较高的主要原因（占癌症死亡总数的18.4%）和最常被诊断出的癌症类型（占癌症总数的11.6%）[1]。非小细胞肺癌（Non-Small Cell Lung Cancer,NSCLC）是其中最主要的一类... 详细信息

背景:全世界的统计数据表明,肺癌仍然是导致癌症发生率和癌症死亡率较高的主要原因（占癌症死亡总数的18.4%）和最常被诊断出的癌症类型（占癌症总数的11.6%）[1]。非小细胞肺癌（Non-Small Cell Lung Cancer,NSCLC）是其中最主要的一类,约占所有肺癌的75–80%[2]。表皮生长因子受体（EGFR,epidermal growth factor receptor）及其信号通路的突变激活是NSCLC最常见的驱动因素。靶向EGFR的小分子酪氨酸激酶受体抑制剂（TKI）在非小细胞肺癌的治疗中取得了非常好的疗效。然而无论前期治疗效果多么显著,大多数病人只能维持半年到一年的有效期,就会产生耐受,使病人获益受限,因此确定EGFR-TKIs对非小细胞肺癌的耐药的具体作用机制,并据此设计相应逆转耐药的策略对NSCLC治疗具有十分重要的意义。目前临床上已根据研究设计了相应的策略用于逆转NSCLC EGFR-TKIs耐药,取得了卓越的疗效,然而再次耐药仍然不可避免,这表明存在其他尚未明确的耐药机制。我们前期研究发现,无论是第一代的EGFR-TKI gefitinib,还是第三代的EGFR TKIs奥西替尼（Osimertinib,AZD9291）,在经药物处理后NSCLC细胞中溶酶体酸化受抑,使促癌蛋白SQSTM1自噬溶酶体降解受阻而表达积聚,导致NSCLC对EGFR-TKIs耐受。敲低SQSTM1在体内外都能通过增加细胞凋亡来增敏EGFR-TKIs对NSCLC的疗效。然而EGFR-TKIs如何抑制溶酶体酸化的具体机制尚未完全明确。目的:通过分析gefitinib和AZD9291的分子构象,我们发现两者和溶酶体抑制剂氯喹（CQ）一样都偏碱性,而CQ正是因为其碱性而抑制溶酶体酸化使溶酶体功能受阻。为了进一步确定EGFR-TKIs是否由于其碱性抑制了溶酶体酸化,从而影响了SQSTM1蛋白的自噬溶酶体降解,导致NSCLC对EGFR-TKIs耐受。我们以gefitinib为例,对gefitinib进行化学改造中和其碱性,并探索酸化改造后的gefitinib与NSCLC的联系,为逆转EGFR-TKIs耐药提供新策略。方法:首先我们利用化学合成的方法在gefitinib上标记罗丹明B（Gefi-RB）分子用于追踪gefitinib在细胞中的定位,同时用Lyso-tracker染色定位溶酶体,观察gefitinib与溶酶体的定位关系。利用化学合成方法改造gefitinib,在其7号位引入两个酸性酚羟基（Gefi-2OH）,中和其碱性,利用MTS、免疫荧光以及western blot等观察改造后的gefitinib衍生物在NSCLC中疗效。结果:利用Gefi-RB和Lyso-tracker共定位实验,我们发现gefitinib的确在溶酶体中富集,而且si RNA敲低EGFR表达并不影响Gefi-RB在溶酶体中的积聚。通过磁共振证实我们的确在gefitinib的7号位上引入了2个呈酸性的酚羟基。我们发现改造后的gefitinib衍生物Gefi-2OH对EGFR信号的抑制与gefitinib相比并没有明显改变。并且通过进一步实验发现,相对于gefitinib,Gefi-2OH对NSCLC细胞增殖的抑制明显增加,对溶酶体酸性的抑制显著减弱,并明显逆转SQSTM1表达积聚。结论:我们发现EGFR-TKIs的确是由于其自身碱性而在溶酶体中富集,从而抑制了溶酶体酸化,使SQSTM1的自噬溶酶体降解受阻而表达积聚,最终导致NSCLC对EGFR-TKIs耐受。此外,对gefitinib进行酸化改造能明显减弱其对溶酶体酸性的影响,从而增敏gefitinib对NSCLC的疗效。我们的研究发现EGFR-TKIs的理化性质如酸碱性等很可能影响其敏感性,从而导致NSCLC产生耐药。因此,对EGFR-TKIs进行化学改造可能会成为增加EGFR-TKIs敏感性并逆转耐药的新思路。

关键词： NSCLC EGFR gefitinib 化学合成溶酶体酸碱性

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients

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Chinese Journal of Cancer Research 2015年第3期27卷 294-300页

作者： Lin Li Zijin Zhang Zhixin Bie Zheng Wang Ping Zhang Xin Nie Yuanming Li Hui Wang Bin Ai Gang Cheng Department of Oncology Beijing Hospital Department of Pathology Beijing Hospital

Background： Epidermal growth factor receptor（EGFR） mutation is the key predictor of EGFR tyrosine kinase inhibitors（TKIs） efficacy in non-small cell lung cancer（NSCLC）. We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods： A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system（ARMS）. We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate（ORR）, disease control rate（DCR） and progression free survival（PFS）.Results： Of all patients, EGFR mutation rate was 28.6%（60/210） by direct sequencing and 45.2%（95/210） by ARMS（P〈0.001） respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR（48.0% vs. 80.9%, P=0.004） and shorter median PFS（7.4 vs. 10.5 months, P=0.009） as compared with that of EGFR mutation positive patients by both detection methods. Conclusions： Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.

关键词： Non-small cell lung cancer （NSCLC） epidermal growth factor receptor （EGFR） mutation cytological specimen amplification refractory mutation system （ARMS） gefitinib