Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient  

作　　者：Fu-jing Ge Xiao-yang Dai Yao Qiu Xiang-ning Liu Chen-ming Zeng Xiao-yuan Xu Yi-dan Chen Hong Zhu Qiao-jun He Ren-hua Gai Sheng-lin Ma Xue-qin Chen Bo Yang 

机构地区：[1]Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China [2]Department of Thoracic Oncology,Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province,Hangzhou Cancer Hospital,Hangzhou,310002,China [3]Innovation Institute for Artificial Intelligence in Medicine,Zhejiang University,Hangzhou,310000,China [4]China Pharmaceutical University,Nanjing,210009,China [5]Cancer Center,Zhejiang University,Hangzhou,310058,China [6]Center for Drug Safety Evaluation and Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China [7]School of Medicine,Hangzhou City University,Hangzhou,310015,China

出　　处：《Acta Pharmacologica Sinica》2024年第6期1252-1263,共12页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(U21A20420);the Science and Technology Development Project of Hangzhou(202204A08).

摘　　要：Although ALK tyrosine kinase inhibitors(ALK-TKIs)have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy,the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers.In this study,we systematically explored the validity of sequential ALK inhibitors(alectinib,lorlatinib,crizotinib,ceritinib and brigatinib)for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models.Based on the patient-derived models and clinical responses of the patient,we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib.In addition,NSCLC patients harboring the G1269A mutation,which was identified in alectinib,lorlatinib and crizotinib-resistant NSCLC,showed responsiveness to brigatinib and ceritinib.Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways,potentially contributing to its anti-tumor activity.Moreover,we constructed a prognostic model based on the expression of IL6,CXCL1,and CXCL5,providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients.In summary,our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALK^(G1269A) mutation and resistant towards alectinib,lorlatinib and crizotinib.The molecular signatures model based on the combination of IL6,CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

关 键 词：EML4-ALK positive NSCLC ALK tyrosine kinase inhibitors drug resistance patient-derived models prognostic biomarkers 

分 类 号：R734.2[医药卫生—肿瘤]