The potential therapeutic regimen for overcoming resistance to osimertinib due to rare mutations in NSCLC

作者全名："Han, Rui; Lin, Caiyu; Zhang, Chong; Kang, Jun; Lu, Conghua; Zhang, Yiming; Wang, Yubo; Hu, Chen; He, Yong"

作者地址："[Han, Rui; Lin, Caiyu; Zhang, Chong; Kang, Jun; Lu, Conghua; Zhang, Yiming; Wang, Yubo; Hu, Chen; He, Yong] Army Med Univ, Daping Hosp, Dept Resp Dis, Chongqing, Peoples R China; [Zhang, Chong] Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："He, Y (通讯作者)，Army Med Univ, Daping Hosp, Dept Resp Dis, Chongqing, Peoples R China."

来源：ISCIENCE

ESI学科分类：　

WOS号：WOS:001056661400001

JCR分区：Q1

影响因子：5.8

年份：2023

卷号：26

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："The mechanisms of osimertinib resistance have not been well characterized. We conducted next-generation sequencing to recognize novel resistance mechanism and used cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models to evaluate the anti-proliferative effects of aspirin in vivo and in vitro. We observed that PIK3CG mutations led to acquired resistance to osimertinib in a patient and further confirmed that both PIK3CG and PIK3CA mutations caused osimertinib resistance. Mechanistically, the expression of PI3Kg or PI3Ka was up-regulated after PIK3CG or PIK3CA lentivirus transfection, respectively, and which can be effectively suppressed by aspirin. Lastly, our results from in vivo studies indicate that aspirin can reverse osimertinib resistance caused by PIK3CG or PIK3CA mutations in both CDX and PDX models. Herein, we first confirmed that mutations in PIK3CG can lead to resistance to osimertinib, and the combined therapy may be a strategy to reverse PIK3CG/PIK3CA mutation induced osimertinib resistance."

基金机构："National Natural Science Foundation of China [81972189, 81802293, 2019CXLCA003]; Clinical medical technology innovation ability training program [2019ZX002]; Key Technology Project for Prevention and Control of Major Diseases in Chongqing [2018XLC1015]; Clinical Medical Research Talent Training Program of Army Medical University [cstc2021jcyj-msxmX0014]; Chongqing Science and Technology Commission [CSTB2022NSCQ-MSX1024, CYB22277]; Chongqing graduate scientific research innovation project; [81902343]"

基金资助正文："The authors thank Hualiang Xiao and Chengyi Mao (Departments of Pathology, Daping Hospital, Army Medical University) for tumor tissues paraffin-embedded and 3-mm formation-fixed paraffin-embedded slides. This work was supported by the National Natural Science Foundation of China (81902343, 81972189 and 81802293), Clinical medical technology innovation ability training program (2019CXLCA003), Key Technology Project for Prevention and Control of Major Diseases in Chongqing (2019ZX002), Clinical Medical Research Talent Training Program of Army Medical University (2018XLC1015), Chongqing Science and Technology Commission(cstc2021jcyj-msxmX0014 and CSTB2022NSCQ-MSX1024), and Chongqing graduate scientific research innovation project (CYB22277). All authors have read and agreed to the published version of the manuscript."