Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas  

作　　者：Yan Li Tongji Xie Shouzheng Wang Lin Yang Xuezhi Hao Yan Wang Xingsheng Hu Lin Wang Junling Li Jianming Ying Puyuan Xing 

机构地区：[1]State Key Laboratory of Molecular Oncology,Department of Pathology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [2]Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [3]Department of Pulmonary and Critical Care Medicine,Beijing Hospital,National Centre of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China [4]Department of Medical Oncology,Beijing Chest Hospital,Capital Medical University,Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing 101149,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第11期5144-5156,共13页信号转导与靶向治疗（英文）

基　　金：the National Natural Science Foundation of China(No.82172876);CAMS Innovation Fund for Medical Sciences(No.2021-1-I2M-012);Beijing Hope Run Special Fund of Cancer Foundation of the People’s Republic of China(LC2019L04,LC2022A20).

摘　　要：Small-cell lung cancer(SCLC)transformation accounts for 3-14%of resistance in EGFR-TKI relapsed lung adenocarcinomas(LUADs),with unknown molecular mechanisms and optimal treatment strategies.We performed transcriptomic analyses(including bulk and spatial transcriptomics)and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFRTKI treatment(LUAD-NT),primary SCLCs(SCLC-P)and LUADs with transformation after EGFR-TKI treatment(before transformation:LUAD-BT;after transformation:SCLC-AT).Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT.We identified several pathways that shifted during transformation,and the transformation might be promoted by epigenetic alterations(such as HDAC10,HDAC1,DNMT3A)within the tumor cells instead of within the tumor microenvironment.For druggable pathways,transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling,while VEGF-VEGFR pathway remained active,indicating potential treatments after transformation.We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation.Besides,SCLC-AT exhibited distinct molecular subtypes from SCLC-P.Moreover,we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation,which obtained a sensitivity of 100%and 87.5%,a specificity of 95.7%and 100%in the training and test cohorts,respectively.We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P,which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.

关 键 词：LUNG ADENOCARCINOMA PREVENTION 

分 类 号：R734.2[医药卫生—肿瘤]