Jun Lu1,2,3, Hua Zhong1,3, Tianqing Chu1, Xueyan Zhang1, Rong Li1, Jiayuan Sun1, Runbo Zhong1, Yuqin Yang2, Mohammad Shah Alam4, Yuqing Lou1, Jianlin Xu1, Yanwei Zhang1, Jun Wu5, Xiaowei Li4, Xiaodong Zhao6,7, Kai Li8,7, Liming Lu2,3,9, Baohui Han1,7. 1. Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. 2. Central laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. 3. Shanghai Institute of Immunology, Shanghai Jiao Ton University School of Medicine, Shanghai, China. 4. Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. 5. School of Life Science, East China Normal University, Shanghai, China. 6. Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China. 7. These authors contributed equally: Jun Lu and Hua Zhong. 8. Dept of Thoracic Oncology, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. 9. These authors contributed equally: Xiaodong Zhao, Kai Li, Liming Lu and Baohui Han.
Abstract
BACKGROUND: Anlotinib has been demonstrated in clinical trials to be effective in prolonging the progression-free survival (PFS) and overall survival (OS) of refractory advanced nonsmall cell lung cancer (NSCLC) patients. However, the underlying molecular mechanisms and predictive biomarkers of anlotinib are still unclear. METHODS: A retrospective analysis of anlotinib administered to 294 NSCLC patients was performed to screen for underlying biomarkers of anlotinib-responsive patients. Transcriptome and functional assays were performed to understand the antitumour molecular mechanisms of anlotinib. Changes in serum CCL2 levels were analysed to examine the correlation of the anlotinib response between responders and nonresponders. RESULTS: Anlotinib therapy was beneficial for prolonging OS in NSCLC patients harbouring positive driver gene mutations, especially patients harbouring the epithelial growth factor receptor (EGFR)T790M mutation. Moreover, anlotinib inhibited angiogenesis in an NCI-H1975-derived xenograft model via inhibiting CCL2. Finally, anlotinib-induced serum CCL2 level decreases were associated with the benefits of PFS and OS in refractory advanced NSCLC patients. CONCLUSIONS: Our study reports a novel anti-angiogenesis mechanism of anlotinib via inhibiting CCL2 in an NCI-H1975-derived xenograft model and suggests that changes in serum CCL2 levels may be used to monitor and predict clinical outcomes in anlotinib-administered refractory advanced NSCLC patients using third-line therapy or beyond.
BACKGROUND:Anlotinib has been demonstrated in clinical trials to be effective in prolonging the progression-free survival (PFS) and overall survival (OS) of refractory advanced nonsmall cell lung cancer (NSCLC) patients. However, the underlying molecular mechanisms and predictive biomarkers of anlotinib are still unclear. METHODS: A retrospective analysis of anlotinib administered to 294 NSCLCpatients was performed to screen for underlying biomarkers of anlotinib-responsive patients. Transcriptome and functional assays were performed to understand the antitumour molecular mechanisms of anlotinib. Changes in serum CCL2 levels were analysed to examine the correlation of the anlotinib response between responders and nonresponders. RESULTS:Anlotinib therapy was beneficial for prolonging OS in NSCLCpatients harbouring positive driver gene mutations, especially patients harbouring the epithelial growth factor receptor (EGFR)T790M mutation. Moreover, anlotinib inhibited angiogenesis in an NCI-H1975-derived xenograft model via inhibiting CCL2. Finally, anlotinib-induced serum CCL2 level decreases were associated with the benefits of PFS and OS in refractory advanced NSCLCpatients. CONCLUSIONS: Our study reports a novel anti-angiogenesis mechanism of anlotinib via inhibiting CCL2 in an NCI-H1975-derived xenograft model and suggests that changes in serum CCL2 levels may be used to monitor and predict clinical outcomes in anlotinib-administered refractory advanced NSCLCpatients using third-line therapy or beyond.
Authors: Jing Xu; Jing-Quan Li; Qi-Lei Chen; Elena A Shestakova; Vsevolod A Misyurin; Vadim S Pokrovsky; Elena M Tchevkina; Hu-Biao Chen; Hang Song; Jian-Ye Zhang Journal: Front Pharmacol Date: 2022-06-13 Impact factor: 5.988