EMBO Molecular Medicine (Jan 2022)
A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC
- Yue Lu,
- Zhenzhen Fan,
- Su‐Jie Zhu,
- Xiaoxing Huang,
- Zhongji Zhuang,
- Yunzhan Li,
- Zhou Deng,
- Lei Gao,
- Xuehui Hong,
- Ting Zhang,
- Li Li,
- Xihuan Sun,
- Wei Huang,
- Jingfang Zhang,
- Yan Liu,
- Baoding Zhang,
- Jie Jiang,
- Fu Gui,
- Zheng Wang,
- Qiyuan Li,
- Siyang Song,
- Xin Huang,
- Qiao Wu,
- Lanfen Chen,
- Dawang Zhou,
- Jianming Zhang,
- Cai‐Hong Yun,
- Liang Chen,
- Xianming Deng
Affiliations
- Yue Lu
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Zhenzhen Fan
- Institute of Life and Health Engineering Jinan University Guangzhou China
- Su‐Jie Zhu
- Department of Biochemistry and Biophysics Institute of Systems Biomedicine Peking University Health Science Center Beijing China
- Xiaoxing Huang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Zhongji Zhuang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Yunzhan Li
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Zhou Deng
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Lei Gao
- Institute of Life and Health Engineering Jinan University Guangzhou China
- Xuehui Hong
- Department of Gastrointestinal Surgery Affiliated Zhongshan Hospital of Xiamen University Xiamen China
- Ting Zhang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Li Li
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Xihuan Sun
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Wei Huang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Jingfang Zhang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Yan Liu
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Baoding Zhang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Jie Jiang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Fu Gui
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Zheng Wang
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Qiyuan Li
- National Institute for Data Science in Health and Medicine School of Medicine Xiamen University Xiamen China
- Siyang Song
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Xin Huang
- Division of Drug Discovery Hongyun Biotech Co., Ltd. Nanjing China
- Qiao Wu
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Lanfen Chen
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Dawang Zhou
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- Jianming Zhang
- National Research Center for Translational Medicine Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
- Cai‐Hong Yun
- Department of Biochemistry and Biophysics Institute of Systems Biomedicine Peking University Health Science Center Beijing China
- Liang Chen
- Institute of Life and Health Engineering Jinan University Guangzhou China
- Xianming Deng
- State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen China
- DOI
- https://doi.org/10.15252/emmm.202114296
- Journal volume & issue
-
Vol. 14,
no. 1
pp. n/a – n/a
Abstract
Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.
Keywords