Protective autophagy decreases lorlatinib cytotoxicity through Foxo3a-dependent inhibition of apoptosis in NSCLC

作者全名："Lu, Conghua; Yu, Rui; Zhang, Chong; Lin, Caiyu; Dou, Yuanyao; Wu, Di; Pan, Yonghong; Peng, Tao; Tang, Huan; Han, Rui; He, Yong"

作者地址："[Lu, Conghua; Yu, Rui; Lin, Caiyu; Dou, Yuanyao; Wu, Di; Pan, Yonghong; Peng, Tao; Tang, Huan; Han, Rui; He, Yong] Army Med Univ, Daping Hosp, Dept Resp Dis, Chongqing 400042, Peoples R China; [Zhang, Chong] Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 1, Chongqing 400042, Peoples R China"

通信作者："Han, R; He, Y (通讯作者)，Army Med Univ, Daping Hosp, Dept Resp Dis, Chongqing 400042, Peoples R China."

来源：CELL DEATH DISCOVERY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000786953100001

JCR分区：Q2

影响因子：7

年份：2022

卷号：8

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Lorlatinib is a promising third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that has been approved for treating ALK-positive non-small-cell lung cancer (NSCLC) patients with previous ALK-TKI treatment failures. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A more comprehensive understanding of the acquired resistance mechanisms to lorlatinib will enable the development of more efficacious therapeutic strategies. The efficacy of chloroquine (CQ) in combination with lorlatinib in ALK-positive NSCLC cells in vitro and in vivo was assessed using CCK-8, colony formation, immunofluorescence staining, flow cytometry analysis, western blot analysis, and xenograft implantation. Here, we show that lorlatinib induced apoptosis and protective autophagy in ALK-positive NSCLC cells. However, the protective autophagy can gradually lead to decreased cytotoxicity of loratinib in ALK-positive NSCLC cells. Meanwhile, we found that the combination of lorlatinib and CQ, an inhibitor of autophagy, inhibited autophagy and promoted apoptosis both in vitro and in vivo, which sensitized cells to lorlatinib through the dephosphorylation of Foxo3a and promoted nuclear translocation, then activation of Foxo3a/Bim axis. Taken together, our results suggest that inhibition of protective autophagy might be a therapeutic target for delaying the occurrence of acquired resistance to lorlatinib in ALK-positive NSCLC patients."

基金机构："Natural Science Foundation of China [81802293, 81902343, 81972189, 82172623]; Chongqing Science Technology Commission [cstc2021jcyj-msxmX0014]; Key Technology Project for Prevention and Control of Major Diseases in Chongqing [2019ZX002]"

基金资助正文："This work was supported by the Natural Science Foundation of China (81802293, 81902343, 81972189, and 82172623), the Chongqing Science Technology Commission (cstc2021jcyj-msxmX0014), and the Key Technology Project for Prevention and Control of Major Diseases in Chongqing (2019ZX002)."