論文 - 詳細
| RRC ID | 66954 |
|---|---|
| 著者 | Yoda S, Lin JJ, Lawrence MS, Burke BJ, Friboulet L, Langenbucher A, Dardaei L, Prutisto-Chang K, Dagogo-Jack I, Timofeevski S, Hubbeling H, Gainor JF, Ferris LA, Riley AK, Kattermann KE, Timonina D, Heist RS, Iafrate AJ, Benes CH, Lennerz JK, Mino-Kenudson M, Engelman JA, Johnson TW, Hata AN, Shaw AT. |
| タイトル | Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. |
| ジャーナル | Cancer Discov |
| Abstract |
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714-29. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663. |
| 巻・号 | 8(6) |
| ページ | 714-729 |
| 公開日 | 2018-6-1 |
| DOI | 10.1158/2159-8290.CD-17-1256 |
| PII | 2159-8290.CD-17-1256 |
| PMID | 29650534 |
| PMC | PMC5984716 |
| MeSH | Aminopyridines Anaplastic Lymphoma Kinase / genetics* Animals Cell Line, Tumor Crizotinib / administration & dosage Crizotinib / pharmacology Drug Resistance, Neoplasm* Ethylnitrosourea / adverse effects Exome Sequencing Female Humans Lactams Lactams, Macrocyclic / administration & dosage* Lactams, Macrocyclic / pharmacology Lung Neoplasms / chemically induced Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Mice Mutation* Oncogene Proteins, Fusion / genetics Protein Kinase Inhibitors / administration & dosage Protein Kinase Inhibitors / pharmacology Pyrazoles Xenograft Model Antitumor Assays |
| IF | 29.497 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 61 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 6.0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3 |