A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC.
Yue LuZhenzhen FanSu-Jie ZhuXiaoxing HuangZhongji ZhuangYunzhan LiZhou DengLei GaoXuehui HongTing ZhangLi LiXihuan SunWei HuangJingfang ZhangYan LiuBaoding ZhangJie JiangFu GuiZheng WangQiyuan LiSiyang SongXin HuangQiao WuLanfen ChenDawang ZhouJianming ZhangCai-Hong YunLiang ChenXianming DengPublished in: EMBO molecular medicine (2021)
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.
Keyphrases
- advanced non small cell lung cancer
- newly diagnosed
- epidermal growth factor receptor
- end stage renal disease
- signaling pathway
- ejection fraction
- small cell lung cancer
- chronic kidney disease
- wild type
- peritoneal dialysis
- prognostic factors
- tyrosine kinase
- cell therapy
- stem cells
- electronic health record
- single cell
- oxidative stress
- mesenchymal stem cells
- climate change
- cell death
- artificial intelligence
- protein kinase
- bone marrow
- endoplasmic reticulum stress
- pi k akt
- cell cycle arrest
- data analysis