A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC
| Autor: | Zhang Jingfang, Yunzhan Li, Zhenzhen Fan, Zhuang Zhongji, Li Li, Ting Zhang, Dawang Zhou, Sun Xihuan, Xianming Deng, Liu Yan, Fu Gui, Deng Zhou, Jie Jiang, Su-Jie Zhu, Huang Xiaoxing, Yue Lu, Siyang Song, Jianming Zhang, Xuehui Hong, Zhang Baoding, Qiao Wu, Lanfen Chen, Wei Huang, Xin Huang, Cai-Hong Yun, Qiyuan Li, Liang Chen, Lei Gao, Zheng Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Medicine (General)
Lung Neoplasms medicine.drug_class Pyridines Mutant Respiratory System acquired resistance mutations EML4‐ALK QH426-470 medicine.disease_cause ALK inhibitor Article Mice R5-920 In vivo Carcinoma Non-Small-Cell Lung hemic and lymphatic diseases medicine Genetics Animals Humans Anaplastic Lymphoma Kinase Pharmacology & Drug Discovery Protein Kinase Inhibitors Cancer Mutation crizotinib Crizotinib business.industry Articles Xenograft Model Antitumor Assays In vitro Protein kinase domain Drug Resistance Neoplasm Cancer research Molecular Medicine Pyrazoles Signal transduction business medicine.drug nonsmall cell lung cancer |
| Zdroj: | EMBO Molecular Medicine, Vol 14, Iss 1, Pp n/a-n/a (2022) EMBO Molecular Medicine |
| ISSN: | 1757-4676 1757-4684 |
| Popis: | 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. Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. |
| Databáze: | OpenAIRE |
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