論文 - 詳細
| RRC ID | 71806 |
|---|---|
| 著者 | Shiba-Ishii A, Johnson TW, Dagogo-Jack I, Mino-Kenudson M, Johnson TR, Wei P, Weinrich SL, McTigue MA, Walcott MA, Nguyen-Phuong L, Dionne K, Acker A, Kiedrowski LA, Do A, Peterson JL, Barth JL, Yeap BY, Gainor JF, Lin JJ, Yoda S, Hata AN. |
| タイトル | Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer. |
| ジャーナル | Nat Cancer |
| Abstract |
Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors. |
| 巻・号 | 3(6) |
| ページ | 710-722 |
| 公開日 | 2022-6-1 |
| DOI | 10.1038/s43018-022-00399-6 |
| PII | 10.1038/s43018-022-00399-6 |
| PMID | 35726063 |
| PMC | PMC9732888 |
| MeSH | Aminopyridines Anaplastic Lymphoma Kinase / genetics Carcinoma, Non-Small-Cell Lung* / drug therapy Drug Resistance, Neoplasm / genetics Humans Lactams Lactams, Macrocyclic / pharmacology Lung Neoplasms* / drug therapy Mutation Protein Kinase Inhibitors / pharmacology Pyrazoles |
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 56 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3(RCB0805) |