2. Academic Validation
  3. A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC

A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC

  • EMBO Mol Med. 2022 Jan 11;14(1):e14296. doi: 10.15252/emmm.202114296.
Yue Lu 1,  Zhenzhen Fan 2,  Su-Jie Zhu 3 4 5,  Xiaoxing Huang 1,  Zhongji Zhuang 1,  Yunzhan Li 1,  Zhou Deng 1,  Lei Gao 2,  Xuehui Hong 6,  Ting Zhang 1,  Li Li 1,  Xihuan Sun 1,  Wei Huang 1,  Jingfang Zhang 1,  Yan Liu 1,  Baoding Zhang 1,  Jie Jiang 1,  Fu Gui 1,  Zheng Wang 1,  Qiyuan Li 7,  Siyang Song 1,  Xin Huang 8,  Qiao Wu 1,  Lanfen Chen 1,  Dawang Zhou 1,  Jianming Zhang 9,  Cai-Hong Yun 3 4,  Liang Chen 2,  Xianming Deng 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • 2 Institute of Life and Health Engineering, Jinan University, Guangzhou, China.
  • 3 Department of Biochemistry and Biophysics, Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, China.
  • 4 Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 5 Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
  • 6 Department of Gastrointestinal Surgery, Affiliated Zhongshan Hospital of Xiamen University, Xiamen, China.
  • 7 National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China.
  • 8 Division of Drug Discovery, Hongyun Biotech Co., Ltd., Nanjing, China.
  • 9 National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
PMID: 34845836 DOI: 10.15252/emmm.202114296
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

ALK inhibitor; EML4-ALK; acquired resistance mutations; crizotinib; nonsmall cell lung cancer.

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