IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Precision tuning of highly efficient Pt-based ternary alloys on nitrogen-doped multi-wall carbon nanotubes for methanol oxidation reaction

The electrochemical methanol oxidation is a crucial reaction in the conversion of renewable energy.To enable the widespread adoption of direct methanol fuel cells(DMFCs),it is essential to create and engineer catalysts that are both highly effective and robust for conducting the methanol oxidation reaction(MOR).In this work,trimetallic PtCoRu electrocatalysts on nitrogen-doped carbon and multi-wall carbon nanotubes(PtCoRu@NC/MWCNTs)were prepared through a two-pot synthetic strategy.The acceleration of CO oxidation to CO_(2) and the blocking of CO reduction on adjacent Pt active sites were attributed to the crucial role played by cobalt atoms in the as-prepared electrocatalysts.The precise control of Co atoms loading was achieved through precursor stoichiometry.Various physicochemical techniques were employed to analyze the morphology,element composition,and electronic state of the catalyst.Electrochemical investigations and theoretical calculations confirmed that the Pt_(1)Co_(3)Ru_(1)@NC/MWCNTs exhibit excellent electrocatalytic performance and durability for the process of MOR.The enhanced MOR activity can be attributed to the synergistic effect between the multiple elements resulting from precisely controlled Co loading content on surface of the electrocatalyst,which facilitates efficient charge transfer.This interaction between the multiple components also modifies the electronic structures of active sites,thereby promoting the conversion of intermediates and accelerating the MOR process.Thus,achieving precise control over Co loading in PtCoRu@NC/MWCNTs would enable the development of high-performance catalysts for DMFCs.

基于创新性内侧壁成型工艺的多光学通道微型碱金属原子气室

Existing microfabricated atomic vapor cells have only one optical channel,which is insufficient for supporting the multiple orthogonal beams required by atomic devices.In this study,we present a novel wafer-level manufacturing process for fabricating multi-optical-channel atomic vapor cells and an innovative method for batch processing the inner sidewalls of millimeter glass holes to meet optical channel requirements.Surface characterization and transmittance tests demonstrate that the processed inner sidewalls satisfy the criteria for an optical channel.In addition,the construction of an integrated processing platform enables multilayer non-isothermal anode bonding,the filling of inert gases,and the recovery and recycling of noble gases.Measurements of the absorption spectra and free-induction decay signals of xenon-129(^(129)Xe)and xenon-131(^(131)Xe)under different pump-probe schemes demonstrate the suitability of our vapor cell for use in atomic devices including atomic gyroscopes,dual-beam atomic magnetometers,and other optical/atomic devices.The proposed micromolding technology has broad application prospects in the field of optical-device processing.

Acetylcholine receptor pathway in lung cancer: New twists to an old story

Genome-wide association studies revealed that allelic variation in the α5-α3-β4 nicotine acetylcholine receptor(n ACh R) cluster on chromosome 15q24-15q25.1 was associated with lung cancer risk. n ACh Rs are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine(ACh) or other biologic compounds including nicotine. n ACh Rs have been found on lung cancer cells, underscoring the idea that the non-neuronal n ACh R pathway has important implications for lung cancer. Several studies focusing on the treatment with n ACh R antagonists with improved selectivity might trigger novel strategies for the intervention and prevention of lung cancer. Here we review the genetic risk factors for lung cancer in the n ACh R gene cluster, the roles of nicotine receptors, and the molecular mechanisms of acetylcholine receptor pathways to lead to more opportunities for intervention and prevention of lung cancer.

Antiangiogenic agents combined with chemotherapy in non-small cell lung cancer

As a targeted therapy, antiangiogenic treatment has been increasingly studied for advanced non-small cell lung cancer(NSCLC) and has proven effective for the treatment of advanced NSCLC. Bevacizumab, a monoclonal antibody targeting angiogenesis, is the only antiangiogenic agent approved for use in combination with first-line chemotherapy for non-squamous NSCLC. Small-molecule inhibitors targeting the tyrosine kinase receptor have also shown promise when combined with standard chemotherapeutic agents in patients with advanced NSCLC. However, unlike bevacizumab, not all other antiangiogenic agents show significant benefits when combined with chemotherapy. As for the failures of most other combinations, the combination schedule may be an important reason that has so far been overlooked in clinical trials. This article reviews the combination of angiogenic agents with chemotherapy in the treatment of NSCLC.

洛拉替尼特殊不良反应管理中国专家共识

间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因是非小细胞肺癌(non-small cell lung cancer,NSCLC)中第二常见的肿瘤驱动基因。作为新型的第三代ALK酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI),洛拉替尼对多种ALK激酶域突变具有广谱且高效的临床活性,并具有强大的穿透血脑屏障效力。洛拉替尼的总体耐受性良好,其独特的不良反应或不良事件包括高脂血症与中枢神经系统反应等,多为轻至中度,通常经剂量调整和/或标准医疗干预即可管理。对于ALK阳性晚期NSCLC,开始洛拉替尼治疗前应充分评估患者基线特征与既往用药状况,预先告知患者可能经历的用药相关不良反应,并定期监测以实现药物临床获益的最大化。同时,多学科专家团队对于建立全面的诊断和治疗策略是至关重要的。

SHR-A1811(antibody-drug conjugate)in advanced HER2-mutant non-small cell lung cancer:a multicenter,open-label,phase 1/2 study

A dose-escalation and expansion,phase 1/2 study(ClinicalTrials.gov,NCT04818333)was conducted to assess the novel antibodydrug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer(NSCLC).Here,we report results from the phase 1 portion.Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks.Dose escalation followed a Bayesian logistic regression model that included overdose control,with subsequent selection of tolerable levels for dose expansion.Overall,63 patients were enrolled,including 43 receiving a recommended dose for expansion of 4.8 mg/kg.All patients had HER2-mutant disease.Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort.Grade≥3 treatment-related adverse events occurred in 29(46.0%)patients.One patient in the 6.4 mg/kg cohort died due to interstitial lung disease.As of April 11,2023,the 4.8 mg/kg cohort showed an objective response rate of 41.9%(95%Cl 27.0-57.9),and a disease control rate of 95.3%(95%Cl 84.2-99.4).The median duration of response was 13.7 months,with 13 of 18 responses ongoing.The median progression-free survival was 8.4 months(95%CI 7.1-15.0).SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutantNSCLC.

Application of next-generation sequencing technology to precision medicine in cancer: joint consensus of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology

Next-generation sequencing(NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously.Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology(CSCO) and the China Actionable Genome Consortium(CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians,pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure(SOP), data analysis, report, and NGS platform certification and validation.

NDFIP1 limits cellular TAZ accumulation via exosomal sorting to inhibit NSCLC proliferation

NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors,but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown.Besides,the WW domain containing proteins can be recognized by NDFIP1,resulted in the loading of the target proteins into exosomes.However,whether WW domain-containing transcription regulator 1(WWTR1,also known as TAZ)can be packaged into exosomes by NDFIP1 and if so,whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent.Here,we first found that NDFIP1 was low expressed in NSCLC samples and cell lines,which is associated with shorter OS.Then,we confirmed the interaction between TAZ and NDFIP1,and the existence of TAZ in exosomes,which requires NDFIP1.Critically,knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate.And the cellular TAZ level could be altered by exosome secretion.Furthermore,NDFIP1 inhibited proliferation in vitro and in vivo,and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout.Moreover,TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples,and the serum exosomal TAZ level was lower in NSCLC patients.In summary,our data uncover a new tumor suppressor,NDFIP1 in NSCLC,and a new exosome-related regulatory mechanism of TAZ.

Efficacy,safety and pharmacokinetics of Unecritinib(TQ-B3101)for patients with ROS1 positive advanced non-small cell lung cancer:a Phase I/II Trial

This phase I/II trial characterized the tolerability,safety,and antitumor activities of unecritinib,a novel derivative of crizotinib and a multi-tyrosine kinase inhibitor targeting ROS1,ALK,and c-MET,in advanced tumors and ROS1 inhibitor-naive advanced or metastatic non-small cell lung cancer(NSCLC)harboring ROS1 rearrangements.Eligible patients received unecritinib 100,200.

用于预测癌症患者临床治疗方案的小鼠mini人源肿瘤异种移植模型的建立

背景与目的患者来源的类器官(patient-derived organoids,PDOs)和异种移植物(patientderivedxenografts,PDXs)具有较强的预测抗癌药物药效的能力,是功能检测的重要模型。然而,移植失败、构建PDX模型和随后检测药效的耗时过长、体外器官培养无法进行系统性给药等限制因素严重阻碍了其在临床上的应用,无法快速地筛选正确、可行的治疗方案。本研究旨在开发一种名为'miniPDX'的改良的PDX模型,用于快速检测药效,提高其在个体化癌症治疗中的应用价值。方法我们开发了一种快速检测体内药物敏感性的方法——OncoVee?MiniPDX,用于筛选癌症临床治疗方案。本模型将患者来源的肿瘤细胞注入中空纤维胶囊内,皮下植入小鼠体内培养7 d。系统评价了细胞的活性形态和药代动力学。以PDX为对照评估miniPDX的性能(敏感性、特异性、阳性和阴性预测值)。分别采用PDX和miniPDX模型以肿瘤生长抑制率和肿瘤细胞生长抑制率为指标检测药物反应。评价miniPDX模型对临床疗效的预测能力。结果MiniPDX胶囊内肿瘤细胞的形态学和组织病理学特征与PDX模型和原发肿瘤细胞的形态学和组织病理学特征均保持一致。26例(包括14例胃癌、10例肺癌和2例胰腺癌)来自患者的PDX肿瘤移植试验的药物反应与相应的miniPDX试验的药物反应结果具有良好的相关性。MiniPDX阳性预测值为92%,阴性预测值为81%,敏感性为80%,特异性为93%。通过扩大临床肿瘤样本,miniPDX检测显示出广泛的临床应用潜力。结论我们建立了基于胶囊植入技术的miniPDX快速体内检测方法,用于评估PDX肿瘤移植物和临床肿瘤标本的药物反应。PDX模型和其对应的miniPDX药效结果具有良好的相关性,结合转化研究数据最终表明miniPDX模型是一种先进的个体化癌症治疗工具。

Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/signal transducer and activator of transcription signaling in inflammatory bowel disease

BACKGROUND Inflammatory bowel disease(IBD)is a prevalent worldwide health problem featured by relapsing,chronic gastrointestinal inflammation.Enhancer of zeste homolog 2(EZH2)is a critical epigenetic regulator in different pathological models,such as cancer and inflammation.However,the role of EZH2 in the IBD development is still obscure.AIM To explore the effect of EZH2 on IBD progression and the underlying mechanism.METHODS The IBD mouse model was conducted by adding dextran sodium sulfate(DSS),and the effect of EZH2 on DSS-induced colitis was assessed in the model.The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit,transepithelial electrical resistance analysis,and Western blot analysis of related markers,including Zona occludens 1,claudin-5,and occludin,in NCM460 and fetal human colon(FHC)cells.The mechanical investigation was performed by quantitative reverse transcriptionpolymerase chain reaction,Western blot analysis,and chromatin immunoprecipitation assays.RESULTS The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system.DSS treatment caused a decreased histological score in the mice,which was reversed by EZH2 depletion.The inflammatory cytokines,such as tumor necrosis factor-α,interleukin-6,and interleukin-1β,were induced in the DSS-treated mice,in which the depletion of EZH2 could reverse this effect.Moreover,the tumor necrosis factor-αtreatment induced the apoptosis of NCM460 and FHC cells,in which EZH2 depletion could reverse this effect in the cells.Moreover,the depletion of EZH2 attenuated permeability of colonic epithelial cells.Mechanically,the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of janus kinase 2(JK2)and signal transducer and activator of transcription in the NCM460 and FHC cells.Specifically,EZH2 inactivated JAK2 expression by regulating histone H3K27me3.JAK2 inhibitor TG101348 was able to reverse EZH2 knockdownmediated colonic epithelial cell permeability and apoptosis.CONCLUSION Thus,we concluded that EZH2 contributed to apoptosis and inflammatory response by inactivating JAK2/signal transducer and activator of transcription signaling in IBD.EZH2 may be applied as a potential target for IBD therapy.

Maintenance Therapy for NSCLC: Consensus and Controversy

Nowadays,advanced non-small cell lung cancer (NSCLC) is still an incurable disease.However,recent researches on maintenance therapy have led to considerable progress.Recently,pemetrexed and erlotinib have been approved for maintenance chemotherapy by both the U.S.Food and Drug Administration and European Medicines Agency.However,there are not adequate data to support the maintenance therapy as the standard treatment for advanced NSCLC and there has been no conclusive predictor of who will get benefit from maintenance chemotherapy and what type of maintenance,continuation or switch,is preferred.This article reviews the main studies on maintenance therapy of advanced NSCLC and discusses the results available to date.

PTGS2 identified as a biomarker of glucocorticoid-induced osteonecrosis of the femoral head and an enhancer of osteogenesis

Due to the use of more adjuvant therapies and the increasing prevalence of associated diseases,nontraumatic osteonecrosis of the femoral head(ONFH)has become a substantial worldwide health issue;while glucocorticoid administration was the highest-ranked risk factor,with a proportion ranging from 26.35 to 55.75%.1 Albeit with similar radiological features,glucocorticoid-induced ONFH(GONFH)manifested a greater probability for advance-tolate-stage(post-collapse)lesions in comparison with its non-glucocorticoid-induced counterparts.i1 Therefore,an accurate and timely diagnosis of osteonecrosis following glucocorticoid therapy is of great significance to initiate nonoperative treatment regimens or joint-preserving procedures,slow disease progression,and defer or avert joint arthroplasty.

导电酞菁基金属有机框架的高效电催化研究

在满足日益增长的可持续能源和环境保护需求下,开发用于多种电化学场景的新型催化剂发挥着重要作用。导电酞菁基金属有机框架(MOFs)是一类新型的层叠多孔MOFs,具有面内扩展π共轭结构,可以通过促进传质和电子/电荷转移来增强电催化活性。导电酞菁基MOFs具有优异的导电性,使其在如水、氧、二氧化碳和氮还原等各种电催化反应中非常有前景。导电酞菁基MOFs在电化学能量转换和环境研究中表现出良好的活性。本文主要关注导电酞菁基MOFs,而非其他类型的导电MOFs,并全面概述其导电机理和主要的电催化反应,还将讨论在电催化中使用导电酞菁基MOFs作为非均相催化剂的最新进展。此外,本文将探讨与导电酞菁基MOFs在电催化中的应用的挑战和展望。

Efficient electroreduction of nitrate via enriched active phases on copper-cobalt oxides

Electrochemical conversion of nitrate(NO_(3)~-) to ammonia(NH_(3)) can target two birds with one stone well, in NO_(3)^(-)-containing sewage remediation and sustainable NH_(3) production. However, single metalbased catalysts are difficult to drive high-efficient NO_(3)~- removal due to the multi-electron transfer steps.Herein, we present a tandem catalyst with simple structure, Cu-Co binary metal oxides(Cu-Co-O), by engineering intermediate phases as catalytic active species for NO_(3)~- conversion. Electrochemical evaluation,X-ray photoelectron spectroscopy, and in situ Raman spectra together suggest that the newly-generated Cu-based phases was prone to NO_(3)~- to NO_(2)~- conversion, then NO_(2)~- was reduced to NH_(3) on Co-based species. At an applied potential of -1.1 V vs. saturated calomel electrode, the Cu-Co-O catalyst achieved NO_(3)~- -N removal of 90% and NH_(3) faradaic efficiency of 81% for 120 min in 100 m L of 50 mg/L NO_(3)~- -N,consuming only 0.69 k Wh/mol in a two-electrode system. This study provides a facile and efficient engineering strategy for developing high-performance catalysts for electrocatalytic nitrate conversion.

Ultrasensitive SERF atomic magnetometer with a miniaturized hybrid vapor cell

The chip-scale hybrid optical pumping spin-exchange relaxation-free(SERF)atomic magnetometer with a single-beam arrangement has prominent applications in biomagnetic measurements because of its outstanding features,including ultrahigh sensitivity,an enhanced signal-to-noise ratio,homogeneous spin polarization and a much simpler optical configuration than other devices.In this work,a miniaturized single-beam hybrid optical pumping SERF atomic magnetometer based on a microfabricated atomic vapor cell is demonstrated.Although the optically thin Cs atoms are spinpolarized,the dense Rb atoms determine the experimental results.The enhanced signal strength and narrowed resonance linewidth are experimentally proven,which shows the superiority of the proposed magnetometer scheme.By using a differential detection scheme,we effectively suppress optical noise with an approximate five-fold improvement.Moreover,the cell temperature markedly affects the performance of the magnetometer.We systematically investigate the effects of temperature on the magnetometer parameters.The theoretical basis for these effects is explained in detail.The developed miniaturized magnetometer has an optimal magnetic sensitivity of 20 fT/Hz^(1/2).The presented work provides a foundation for the chip-scale integration of ultrahighly sensitive quantum magnetometers that can be used for forward-looking magnetocardiography(MCG)and magnetoencephalography(MEG)applications.

Peripheral CD4^(+) T cell signatures in predicting the responses to anti-PD-1/PD-L1 monotherapy for Chinese advanced non-small cell lung cancer

Limited benefit population of immune checkpoint inhibitors makes it urgent to screen predictive biomarkers for stratifying the patients.Herein,we have investigated peripheral CD4^(+) T cell signatures in advanced non-small cell lung cancer(NSCLC)patients receiving anti-PD-1/PD-L1 treatments.It was found that the percentages of IFN-γand IL-17A secreting naïve CD4^(+) T cells(Tn),and memory CD4^(+) T cells(Tm)expressing PD-1,PD-L1 and CTLA-4 were significantly higher in responder(R)than non-responder(NonR)NSCLC patients associated with a longer progression free survival(PFS).Logistic regression analysis revealed that the baseline IFN-γ-producing CD4^(+) Tn cells and PD-1^(+)CD4^(+) Tm cells were the most significant signatures with the area under curve(AUC)value reaching 0.849.This was further validated in another anti-PD-1 monotherapy cohort.Conversely,high percentage of CTLA-4^(+)CD4^(+) Tm cells was associated with a shorter PFS in patients receiving anti-PD-L1 monotherapy.Our study therefore elucidates the significance of functional CD4^(+) Tn and Tm subpopulations before the treatment in predicting the responses to anti-PD-1 treatment in Chinese NSCLC patients.The fact that there display distinct CD4^(+) T cell signatures in the prediction to anti-PD-1 and anti-PD-L1 monotherapy from our study provides preliminary evidence on the feasibility of anti-PD-1 and anti-PD-L1 combination therapy for advanced NSCLC patients.

Effectiveness of PD-1/PD-L1 inhibitors in the treatment of lung cancer:Brightness and challenge

Immune checkpoint inhibitors(ICIs),especially inhibitors of the PD-1/PD-L1 axis,have significantly affected the outcomes of patients with lung cancer.Nivolumab and pembrolizumab have been approved as PD-1 blocking antibodies,whereas atezolizumab,avelumab,and durvalumab are approved as PD-L1 blocking antibodies by the United States Food and Drug Administration.However,which patient may benefit the most and how to identify patients at risk of primary or acquired resistance has not been completely defined.Meanwhile,close attention has been paid to the ongoing international and domestic clinical trials in Chinese patients with lung cancer.This review aimed to provide deep insight into the effectiveness of PD-1/PD-L1 inhibitors in patients with lung cancer,including the current settings for varied disease status,the predictive biomarkers,the resistance to ICIs,and the ongoing clinical trials in Chinese patients.

Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance

Background:Non-small cell lung cancer(NSCLC)patients with epidermal growth factor receptor(EGFR)mutations or anaplastic lymphoma kinase(ALK)fusions show dramatic responses to specific tyrosine kinase inhibitors(TKIs);however,after 10-12 months,secondary mutations arise that confer resistance.We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK-and EGFR-targeted TKIs crizotinib and osimertinib,respectively.Methods:Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing(WES),and patients and xenograft-bearing mice received targeted treatment(crizotinib or osimertinib)accordingly.Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size.Finally,the pathology of patients biopsies and xenograft tumors were compared histologically.Results:The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients.WES showed that the genotypes of the xenograft and patient tumors were similar(an echinoderm microtu-bule-associated protein-like 4-ALK(EML4-ALK)gene fusion(patient/xenograft:CTC15035EML4-ALK)and EGFR L858R and T790M mutations(patient/xenograft:CTC15063EGFR L858R,T790M)).After continuous crizotinib or osimertinib treatment,WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035EML4-ALK xenograft,while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B(BRAF)G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha(PIK3C2A)A86fs frame shift mutations led to osimertinib resistance in the CTC15063EGFR L858R,T790M xenografts.Conclusions:We successfully developed a new method of generating drug resistance xenograft models from liquid biopsies using microfluidic technology,which might be a useful tool to investigate the mechanisms of drug resist-ance in NSCLC.