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Tet methylcytosine dioxygenase 2(TET2)deficiency elicits EGFR-TKI(tyrosine kinase inhibitors)resistance in non-small cell lung cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1706-1720页

作者： Jian Zhang Kejia Zhao Wenjing Zhou Ran Kang Shiyou Wei Yueli Shu Cheng Yu Yin Ku Yonghong Mao Hao Luo Juqin Yang Jiandong Mei Qiang Pu Senyi Deng Zhengyu Zha Gang Yuan Shensi Shen Yaohui Chen Lunxu Liu Department of thoracic Surgery and Institute of thoracic oncology West China Hospital of Sichuan UniversityChengdu 610097China Western China Collaborative Innovation center for Early Diagnosis and Multidisciplinary Therapy of Lung Cancer Sichuan UniversityChengdu 610097China Biobank of West China Hospital Sichuan UniversityChengdu 610041China

Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKl)have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer(NSCLC),acquired resistance inevitably develops,limiting clinical efficacy.We found that TET2 was poly-ubiquitinated by E3 ligase CUL7^(FBXW11) and degraded in EGFR-TKI resistant NSCLC ells.Genetic perturbationof TET2 rendered parental cells more tolerant to TKI treatment.TET2 was stabilized by MEK1 phosphorylation at Ser 1107,while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7^(FBXW11),Loss of TET2 resulted in the upregulation of TNF/NF-kB signaling that confers the EGFR-TKI resistance.Genetic or pharmacological inhibition of NF-kB attenuate the TKI resistance both in vitro and in vivo.Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2,and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency.Therefore,combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.

关键词： TET2 TKI resistance

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Prognostic role of C-reactive protein to albumin ratio in lung cancer:An updated systematic review and meta-analysis

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Chronic Diseases and Translational Medicine 2024年第1期10卷 31-39页

作者： Zhendong Lu Siyun Fu Wei Li Xiang Gao Jinghui Wang Department of Medical oncology Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijing Chest HospitalCapital Medical UniversityBeijingChina Cancer Research center Beijing Chest HospitalBeijing Tuberculosis and Thoracic Tumor Research InstituteCapital Medical UniversityBeijingChina

Background: C-reactive protein to albumin ratio(CRP/Alb ratio,CAR)has been suggested as a potential prognostic biomarker in lung cancer.This updated systematic review and meta-analysis aimed to assess the association between CAR and lung cancer prognosis in current literature.Methods: A systematic search of databases was conducted to identify relevant studies published up to April 2023.Pooled hazard ratios(HRs)and 95%confidence intervals(CIs)were calculated to assess the association between CAR and overall survival(OS)and progression-free survival(PFS)and recurrence-free survival(RF)in lung cancer patients.Results: This meta-analysis includes 16 studies with a total of 5337 patients,indicating a significant association between higher CAR and poorer OS,PFS,and RFS in lung cancer patients,with a pooled HR of 1.78(95%CI=1.60-1.99),1.57(95%CI=1.36-1.80),and 1.97(95%CI=1.40-2.77),respectively.Conclusions: This updated meta-analysis provides evidence for the potential prognostic role of CAR in lung cancer,suggesting its utility as an effective and noninvasive biomarker for identifying high-risk patients and informing treatment decisions in a cost-effective manner.However,further large-scale studies will be necessary to establish the optimal cut-off value for CAR in lung cancer and confirm the present findings.

关键词： C-reactive protein to albumin ratio inflammation:biomarker lung cancer prognosis

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Neoantigen cancer vaccines:a new star on the horizon

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Cancer Biology & Medicine 2024年第4期21卷 274-311页

作者： Xiaoling Li Jian You Liping Hong Weijiang Liu Peng Guo Xishan Hao Cell Biotechnology Laboratory Tianjin Cancer Hospital Airport HospitalTianjin 300308China National Clinical Research center for Cancer Tianjin 300060China Haihe Laboratory of Synthetic Biology Tianjin 300090China Department of thoracic oncology Tianjin Cancer Hospital Airport HospitalTianjin 300308China Department of thoracic oncology Surgery Tianjin Medical University Cancer Institute&HospitalTianjin 300060China Tianjin Medical University Cancer Institute&Hospital Tianjin 300060China

Immunotherapy represents a promising strategy for cancer treatment that utilizes immune cells or drugs to activate the patient's own immune system and eliminate cancer cells.One of the most exciting advances within this field is the targeting of neoantigens,which are peptides derived from non-synonymous somatic mutations that are found exclusively within cancer cells and absent in normal cells.Although neoantigen-based therapeutic vaccines have not received approval for standard cancer treatment,early clinical trials have yielded encouraging outcomes as standalone monotherapy or when combined with checkpoint inhibitors.Progress made in high-throughput sequencing and bioinformatics have greatly facilitated the precise and efficient identification of neoantigens.Consequently,personalized neoantigen-based vaccines tailored to each patient have been developed that are capable of eliciting a robust and long-lasting immune response which effectively eliminates tumors and prevents recurrences.This review provides a concise overview consolidating the latest clinical advances in neoantigen-based therapeutic vaccines,and also discusses challenges and future perspectives for this innovative approach,particularly emphasizing the potential of neoantigen-based therapeutic vaccines to enhance clinical efficacy against advanced solid tumors.

关键词： Immunotherapy neoantigen cancer vaccine solid tumors high-throughput sequencing bioinformatics PDOs AI HLA TCR

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液体活检在肺癌管理中新技术的发展和临床应用的拓展

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Science Bulletin 2024年第10期69卷 1556-1568页

作者：陈克终何越王文香袁晓秋 David P.Carbone 杨帆 Department of thoracic Surgery Peking University People’s HospitalBeijing 100044China Peking University People’s Hospital thoracic oncology Institute&Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer Beijing 100044China Peking University Health Science center Beijing 100191China thoracic oncology center Ohio State UniversityColumbus 43026USA

Lung cancer is an exceedingly malignant tumor reported as having the highest morbidity and mortality of any cancer worldwide,thus posing a great threat to global health.Despite the growing demand for precision medicine,current methods for early clinical detection,treatment and prognosis monitoring in lung cancer are hampered by certain bottlenecks.Studies have found that during the formation and development of a tumor,molecular substances carrying tumor-related genetic information can be released into body fluids.Liquid biopsy(LB),a method for detecting these tumor-related markers in body fluids,maybe a way to make progress in these bottlenecks.In recent years,LB technology has undergone rapid advancements.Therefore,this review will provide information on technical updates to LB and its potential clinical applications,evaluate its effectiveness for specific applications,discuss the existing limitations of LB,and present a look forward to possible future clinical applications.Specifically,this paper will introduce technical updates from the prospectives of engineering breakthroughs in the detection of membrane-based LB biomarkers and other improvements in sequencing technology.Additionally,it will summarize the latest applications of liquid biopsy for the early detection,diagnosis,treatment,and prognosis of lung cancer.We will present the interconnectedness of clinical and laboratory issues and the interplay of technology and application in LB today.

关键词： Liquid biopsy techniques Lung cancer Circulating tumor cells Circulating tumor DNA Sequencing technology Clinical application

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First-line immunotherapy for advanced non-small cell lung cancer:current progress and future prospects

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Cancer Biology & Medicine 2024年第2期21卷 117-124页

作者： Jingyi Wang Lin Wu The Second Department of thoracic oncology Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China Xiangya Lung Cancer center Xiangya HospitalCentral South UniversityChangsha 410008China

Global Cancer Statistics 2022 reported the prevalence and high mortality rate of lung cancer.Notably,non-small cell lung cancer(NSCLC)accounts for the majority of the histologic types1.Precision therapy for lung cancer has progressed rapidly and immune checkpoint inhibitors(ICIs)have become a leading research topic.Indeed,ICI therapy has been shown to improve the prognosis of lung cancer patients.

关键词： lung cancer mortality

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Mechanism of PARP inhibitor resistance and potential overcoming strategies

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Genes & Diseases 2024年第1期11卷 306-320页

作者： Xiaoyu Fu Ping Li Qi Zhou Ruyuan He Guannan Wang Shiya Zhu Amir Bagheri Gary Kupfer Huadong Pei Juanjuan Li Department of oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA Department of Breast and Thyroid Surgery Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Cancer center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Department of thoracic Surgery Renmin Hospital of Wuhan UniversityWuhanHubei 430060China

PARP inhibitors(PARPi)are a kind of cancer therapy that targets poly(ADP-ribose)polymerase.PARPi is the first clinically approved drug to exert synthetic lethality by obstruct-ing the DNA single-strand break repair process.Despite the significant therapeutic effect in pa-tients with homologous recombination(HR)repair deficiency,innate and acquired resistance to PARPi is a main challenge in the clinic.In this review,we mainly discussed the underlying mechanisms of PARPi resistance and summarized the promising solutions to overcome PARPi resistance,aiming at extending PARPi application and improving patient outcomes.

关键词： Drug resistance Homologous recombination PARP PARP inhibitor Poly(ADP-ribose)polymerase

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Association of previously irradiated stable brain metastases with outcomes of atezolizumab-treated non-small cell lung cancer: A pooled analysis of individual patient data from three randomized trials

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Cancer Communications 2024年第2期44卷 278-281页

作者： Tiantian Guo Yue Zhou Fei Liang Zezhou Wang Vincent Bourbonne Lukas Käsmann Nora Sundahl Abraham Jing-Ching Wu Jianjiao Ni Zhengfei Zhu Department of Radiation oncology Fudan University Shanghai Cancer CenterShanghaiP.R.China Department of oncology Shanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Clinical Research center for Radiation oncology ShanghaiP.R.China Shanghai Key Laboratory of Radiation oncology ShanghaiP.R.China Department of Biostatistics Zhongshan HospitalFudan UniversityShanghaiP.R.China Department of Cancer Prevention Fudan University Shanghai Cancer CenterShanghaiP.R.China Radiation oncology Department University HospitalBrestFrance Department of Radiation oncology University HospitalLMU MunichMunichGermany Department of Radiation oncology AZ GroeningeKortrijkBelgium Department of Radiation oncology Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA Institute of thoracic oncology Fudan UniversityShanghaiP.R.China

Dear Editor:Brain metastasis(BM)has long been recognized as a prognostic factor associated with poor prognosis for non-small cell lung cancer(NSCLC)in the era of con-ventional chemotherapy and targeted therapy[1].In the era of immunotherapy,controversial findings have been reported regarding the prognostic significance of BM in patients with NSCLC treated with programmed death-1/programmed death-ligand 1(PD-1/PD-L1)inhibitors.

关键词： chemotherapy NSCLC metastasis death

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The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions:insights from a single-arm,phase II trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2202-2214页

作者： Bo Cheng Caichen Li Jianfu Li Longlong Gong Peng Liang Ying Chen Shuting Zhan Shan Xiong Ran Zhong Hengrui Liang Yi Feng Runchen Wang Haixuan Wang Hongbo Zheng Jun Liu Chengzhi Zhou Wenlong Shao Yuan Qiu Jiancong Sun Zhanhong Xie Zhu Liang Chenglin Yang Xiuyu Cai Chunxia Su Wei Wang Jianxing He Wenhua Liang Department of thoracic Surgery and oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina Medical Department Genecast Biotechnology Co.LtdWuxiChina Department of Radiation oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Department of Respiratory Medicine the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina Department of Cardiothoracic Surgery Affiliated Hospital of Guangdong Medical UniversityZhanjiangChina Department of thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina Department of VIP Inpatient Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaSun Yat-sen UniversityGuangzhouChina Department of Medical oncology Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina

Immune checkpoint inhibitors targeting the programmed cell death-1(PD-1)protein significantly improve survival in patients with advanced non-small-cell lung cancer(NSCLC),but its impact on early-stage ground-glass opacity(GGO)lesions remains unclear.This is a single-arm,phase II trial(NCT04026841)using Simon’s optimal two-stage design,of which 4 doses of sintilimab(200 mg per 3 weeks)were administrated in 36 enrolled multiple primary lung cancer(MPLC)patients with persistent high-risk(Lung-RADS category 4 or had progressed within 6 months)GGOs.The primary endpoint was objective response rate(ORR).T/B/NK-cell subpopulations,TCR-seq,cytokines,exosomal RNA,and multiplexed immunohistochemistry(mIHC)were monitored and compared between responders and non-responders.Finally,two intent-to-treat(ITT)lesions(pure-GGO or GGO-predominant)showed responses(ORR:5.6%,2/36),and no patients had progressive disease(PD).No grade 3-5 TRAEs occurred.The total response rate considering two ITT lesions and three non-intent-to-treat(NITT)lesions(pure-solid or solid-predominant)was 13.9%(5/36).The proportion of CD8^(+)T cells,the ratio of CD8^(+)/CD4^(+),and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time.Correspondingly,the mIHC analysis showed more CD8^(+)T cells infiltrated in responders.Besides,responders’cytokine concentrations of EGF and CTLA-4 increased during treatment.The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders.Collectively,PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns.Such effects were associated with specific T-cell re-distribution,EGF/CTLA-4 cytokine compensation,and regulation of metabolism pathways.

关键词： lesions metabolism doses

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Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

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Cancer Communications 2024年第2期44卷 287-293页

作者： Kouya Shiraishi Atsushi Takahashi Yukihide Momozawa Yataro Daigo Syuzo Kaneko Takahisa Kawaguchi Hideo Kunitoh Shingo Matsumoto Hidehito Horinouchi Akiteru Goto Takayuki Honda Kimihiro Shimizu Masahiro Torasawa Daisuke Takayanagi Motonobu Saito Akira Saito Yuichiro Ohe Shun-ichi Watanabe Koichi Goto Masahiro Tsuboi Katsuya Tsuchihara Sadaaki Takata Tomomi Aoi Atsushi Takano Masashi Kobayashi Yohei Miyagi Kazumi Tanaka Hiroyuki Suzuki Daichi Maeda Takumi Yamaura Maiko Matsuda Yoko Shimada Takaaki Mizuno Hiromi Sakamoto Teruhiko Yoshida Yasushi Goto Tatsuya Yoshida Taiki Yamaji Makoto Sonobe Shinichi Toyooka Kazue Yoneda Katsuhiro Masago Fumihiro Tanaka Megumi Hara Nobuo Fuse Satoshi S.Nishizuka Noriko Motoi Norie Sawada Yuichiro Nishida Kazuki Kumada Kenji Takeuchi Kozo Tanno Yasushi Yatabe Kuniko Sunami Tomoyuki Hishida Yasunari Miyazaki Hidemi Ito Mitsuhiro Amemiya Hirohiko Totsuka Haruhiko Nakayama Tomoyuki Yokose Kazuyoshi Ishigaki Toshiteru Nagashima Yoichi Ohtaki Kazuhiro Imai Ken Takasawa Yoshihiro Minamiya Kazuma Kobayashi Kenichi Okubo Kenji Wakai Atsushi Shimizu Masayuki Yamamoto Motoki Iwasaki Koichi Matsuda Johji Inazawa Yuichi Shiraishi Hiroyoshi Nishikawa Yoshinori Murakami Michiaki Kubo Fumihiko Matsuda Yoichiro Kamatani Ryuji Hamamoto Keitaro Matsuo Takashi Kohno Division of Genome Biology National Cancer Center Research InstituteTokyoJapan Department of Clinical Genomics National Cancer Center Research InstituteTokyoJapan Laboratory for Statistical Analysis Center for Integrative Medical SciencesRIKENYokohamaJapan Department of Genomic Medicine Research InstituteNational Cerebral and Cardiovascular CenterOsakaJapan Laboratory for Genotyping Development Center for Integrative Medical SciencesRIKENYokohamaJapan center for Antibody and Vaccine Therapy Research HospitalInstitute of Medical ScienceThe University of TokyoTokyoJapan Department of Medical oncology and Cancer center and Center for Advanced Medicine against CancerShiga University of Medical ScienceOtsuJapan Division of Medical AI Research and Development National Cancer Center Research InstituteTokyoJapan center for Genomic Medicine Graduate School of MedicineKyoto UniversityKyotoJapan Department of Medical oncology Japanese Red Cross Medical CenterTokyoJapan Department of thoracic oncology National Cancer Center Hospital EastJapan Department of thoracic oncology National Cancer Center HospitalTokyoJapan Department of Cellular and Organ Pathology Graduate School of MedicineAkita UniversityAkitaJapan Department of Respiratory Medicine Tokyo Medical and Dental UniversityBunkyo-kuTokyoJapan Division of General thoracic Surgery Department of SurgeryShinshu University School of MedicineMatsumotoNaganoJapan Department of General Surgical Science Division of General Thoracic SurgeryGunma University Graduate School of MedicineIntegrative Center of General SurgeryGunma University HospitalGunmaJapan Department of Gastrointestinal Tract Surgery Fukushima Medical University School of MedicineFukushimaJapan StaGen Co. LtdTokyoJapan Division of thoracic Surgery National Cancer Center HospitalTokyoJapan Department of thoracic Surgery National Cancer Center Hospital EastChibaJapan Division of Translational Informatics Exploratory Oncology Research and Clinical Trial Center(EPOC

Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.

关键词： adenocarcinoma lung Lung

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Effectiveness and safety of combined nimotuzumab and S-1 chemotherapy with concurrent radiotherapy for locally advanced esophageal cancer in malnourished and elderly patients:A prospective phase Ⅱ study

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Chinese Journal of Cancer Research 2024年第3期36卷 270-281页

作者： Guojie Feng Jiao Li Nuo Yu Ziyu Zheng Xiongtao Yang Lei Deng Tao Zhang Wenqing Wang Wenyang Liu Jianyang Wang Qinfu Feng Jima Lyu Zefen Xiao Zongmei Zhou Nan Bi Jianjun Qin Xin Wang Department of Radiation oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Department of thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

Objective: Definitive chemoradiotherapy(dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002(NRS-2002) score.Methods: Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control(LRC) rate.Results: A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3[95% confidence interval(95% CI), 31.4-35.1)] months. The LRC rate was 77.2%(95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival(OS) rate and event-free survival(EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio(HR)=0.16; 95% CI,0.04-0.70; P=0.015], OS(HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS(HR=0.25; 95% CI, 0.08-0.75;P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred.Conclusions: For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.

关键词： Esophageal carcinoma squamous cell carcinoma nutritional risk score nimotuzumab S-1 definitive chemoradiotherapy

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