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Ref Type Journal Article
PMID (34845836)
Authors Lu Y, Fan Z, Zhu SJ, Huang X, Zhuang Z, Li Y, Deng Z, Gao L, Hong X, Zhang T, Li L, Sun X, Huang W, Zhang J, Liu Y, Zhang B, Jiang J, Gui F, Wang Z, Li Q, Song S, Huang X, Wu Q, Chen L, Zhou D, Zhang J, Yun CH, Chen L, Deng X
Title A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC.
Journal EMBO molecular medicine
Vol
Issue
Date 2021 Nov 30
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
XMU-MP-5 ALK Inhibitor 26 XMU-MP-5 is a small molecule inhibitor of ALK with activity against ALK fusions and secondary ALK mutations, which may lead to inhibition of tumor cell growth and tumor regression (PMID: 34845836).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK F1174L Advanced Solid Tumor predicted - resistant XMU-MP-5 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174L did not demonstrate sensitivity to treatment with XMU-MP-5 in culture (PMID: 34845836). 34845836
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive XMU-MP-5 Preclinical - Cell culture Actionable In a preclinical study, XMU-MP-5 treatment decreased downstream signaling and inhibited proliferation of transformed cells expressing EML4-ALK with ALK C1156Y in culture (PMID: 34845836). 34845836
EML4 - ALK lung non-small cell carcinoma sensitive XMU-MP-5 Preclinical - Cell line xenograft Actionable In a preclinical study, XMU-MP-5 treatment decreased downstream signaling, induced apoptosis, and inhibited proliferation of non-small cell lung caner cells harboring EML4-ALK in culture, and inhibited tumor growth in cell line xenograft models (PMID: 34845836). 34845836
EML4 - ALK ALK G1269A Advanced Solid Tumor sensitive XMU-MP-5 Preclinical - Cell culture Actionable In a preclinical study, XMU-MP-5 treatment decreased downstream signaling and inhibited proliferation of transformed cells expressing EML4-ALK with ALK G1269A in culture (PMID: 34845836). 34845836
EML4 - ALK ALK G1202R Advanced Solid Tumor sensitive XMU-MP-5 Preclinical - Cell line xenograft Actionable In a preclinical study, XMU-MP-5 treatment decreased downstream signaling and inhibited proliferation of transformed cells expressing EML4-ALK with ALK G1202R in culture, and inhibited tumor growth in cell line xenograft models (PMID: 34845836). 34845836
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive XMU-MP-5 Preclinical - Cell line xenograft Actionable In a preclinical study, XMU-MP-5 treatment decreased downstream signaling and inhibited proliferation of transformed cells expressing EML4-ALK with ALK L1196M in culture, and inhibited tumor growth in cell line xenograft models (PMID: 34845836). 34845836
EML4 - ALK ALK I1171T Advanced Solid Tumor sensitive XMU-MP-5 Preclinical - Cell culture Actionable In a preclinical study, XMU-MP-5 treatment decreased downstream signaling and inhibited proliferation of transformed cells expressing EML4-ALK with ALK I1171T in culture (PMID: 34845836). 34845836
EML4 - ALK Advanced Solid Tumor sensitive XMU-MP-5 Preclinical - Cell culture Actionable In a preclinical study, XMU-MP-5 treatment decreased downstream signaling, induced apoptosis, and inhibited viability of transformed cells expressing EML4-ALK in culture (PMID: 34845836). 34845836