TY - JOUR
T1 - A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC
AU - Lu, Yue
AU - Fan, Zhenzhen
AU - Zhu, Su Jie
AU - Huang, Xiaoxing
AU - Zhuang, Zhongji
AU - Li, Yunzhan
AU - Deng, Zhou
AU - Gao, Lei
AU - Hong, Xuehui
AU - Zhang, Ting
AU - Li, Li
AU - Sun, Xihuan
AU - Huang, Wei
AU - Zhang, Jingfang
AU - Liu, Yan
AU - Zhang, Baoding
AU - Jiang, Jie
AU - Gui, Fu
AU - Wang, Zheng
AU - Li, Qiyuan
AU - Song, Siyang
AU - Huang, Xin
AU - Wu, Qiao
AU - Chen, Lanfen
AU - Zhou, Dawang
AU - Zhang, Jianming
AU - Yun, Cai Hong
AU - Chen, Liang
AU - Deng, Xianming
N1 - Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2022/1/11
Y1 - 2022/1/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120174324&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120174324&partnerID=8YFLogxK
U2 - 10.15252/emmm.202114296
DO - 10.15252/emmm.202114296
M3 - Article
C2 - 34845836
AN - SCOPUS:85120174324
SN - 1757-4676
VL - 14
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 1
M1 - e14296
ER -