A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2021-11-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114296 |
| _version_ | 1827045161102737408 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Yue Lu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T18:42:50Z |
| format | Article |
| id | doaj.art-c6601c62cfee423f8b9920da0e450eea |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:20:04Z |
| publishDate | 2021-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-c6601c62cfee423f8b9920da0e450eea2024-10-28T08:51:23ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-11-0114111310.15252/emmm.202114296A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLCYue Lu0Zhenzhen Fan1Su‐Jie Zhu2Xiaoxing Huang3Zhongji Zhuang4Yunzhan Li5Zhou Deng6Lei Gao7Xuehui Hong8Ting Zhang9Li Li10Xihuan Sun11Wei Huang12Jingfang Zhang13Yan Liu14Baoding Zhang15Jie Jiang16Fu Gui17Zheng Wang18Qiyuan Li19Siyang Song20Xin Huang21Qiao Wu22Lanfen Chen23Dawang Zhou24Jianming Zhang25Cai‐Hong Yun26Liang Chen27Xianming Deng28State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityInstitute of Life and Health Engineering, Jinan UniversityDepartment of Biochemistry and Biophysics, Institute of Systems Biomedicine, Peking University Health Science CenterState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityInstitute of Life and Health Engineering, Jinan UniversityDepartment of Gastrointestinal Surgery, Affiliated Zhongshan Hospital of Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityNational Institute for Data Science in Health and Medicine, School of Medicine, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityDivision of Drug Discovery, Hongyun Biotech Co., Ltd.State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityNational Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Biochemistry and Biophysics, Institute of Systems Biomedicine, Peking University Health Science CenterInstitute of Life and Health Engineering, Jinan UniversityState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen UniversityAbstract 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.https://doi.org/10.15252/emmm.202114296acquired resistance mutationsALK inhibitorcrizotinibEML4‐ALKnonsmall cell lung cancer |
| spellingShingle | 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 A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC EMBO Molecular Medicine acquired resistance mutations ALK inhibitor crizotinib EML4‐ALK nonsmall cell lung cancer |
| title | A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
| title_full | A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
| title_fullStr | A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
| title_full_unstemmed | A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
| title_short | A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
| title_sort | new alk inhibitor overcomes resistance to first and second generation inhibitors in nsclc |
| topic | acquired resistance mutations ALK inhibitor crizotinib EML4‐ALK nonsmall cell lung cancer |
| url | https://doi.org/10.15252/emmm.202114296 |
| work_keys_str_mv | AT yuelu anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhenzhenfan anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT sujiezhu anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xiaoxinghuang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhongjizhuang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT yunzhanli anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhoudeng anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT leigao anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xuehuihong anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT tingzhang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT lili anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xihuansun anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT weihuang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT jingfangzhang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT yanliu anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT baodingzhang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT jiejiang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT fugui anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhengwang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT qiyuanli anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT siyangsong anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xinhuang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT qiaowu anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT lanfenchen anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT dawangzhou anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT jianmingzhang anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT caihongyun anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT liangchen anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xianmingdeng anewalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT yuelu newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhenzhenfan newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT sujiezhu newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xiaoxinghuang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhongjizhuang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT yunzhanli newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhoudeng newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT leigao newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xuehuihong newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT tingzhang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT lili newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xihuansun newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT weihuang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT jingfangzhang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT yanliu newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT baodingzhang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT jiejiang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT fugui newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT zhengwang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT qiyuanli newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT siyangsong newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xinhuang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT qiaowu newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT lanfenchen newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT dawangzhou newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT jianmingzhang newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT caihongyun newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT liangchen newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc AT xianmingdeng newalkinhibitorovercomesresistancetofirstandsecondgenerationinhibitorsinnsclc |