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 LiSiyang Song, Xin Huang, Qiao Wu, Lanfen Chen, Dawang Zhou, Jianming Zhang, Cai Hong Yun, Liang Chen, Xianming Deng

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Article numbere14296
JournalEMBO Molecular Medicine
Volume14
Issue number1
DOIs
StatePublished - Jan 11 2022

ASJC Scopus subject areas

  • Molecular Medicine

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