Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
EMBO molecular medicine			2021 Nov 30	e14296	EMBO Mol Med

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
XMU-MP-5	XMU-MP-5	8	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
XMU-MP-5			ALK Inhibitor 32	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 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 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	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
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 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 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	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 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