Reference - Detail
| RRC ID | 86335 |
|---|---|
| Author | Tangpeerachaikul A, Mente S, Magrino J, Gu F, Horan JC, Pelish HE. |
| Title | Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations. |
| Journal | Mol Cancer Ther |
| Abstract |
Zidesamtinib (NVL-520) is a ROS1-selective macrocyclic tyrosine kinase inhibitor designed with the aim to address clinical challenges for patients with non-small cell lung or other cancers that are ROS1 fusion-positive. These challenges include emergent ROS1 resistance mutations and brain metastases that can lead to disease progression and central nervous system adverse events attributed to off-target tropomyosin-related kinase inhibition that can be treatment-limiting. We evaluated zidesamtinib in accelerated mutagenesis screens and a brain tumor model, comparing it with other approved or investigational ROS1 inhibitors. At clinically relevant concentrations, zidesamtinib robustly inhibited >1,500 pooled ROS1 mutants with virtually no resistance emerging (≤1%), outperforming comparators crizotinib, entrectinib, and repotrectinib. Zidesamtinib also induced more durable responses than repotrectinib and taletrectinib in an aggressive intracranial ROS1 G2032R xenograft model. A 2.2 Å cocrystal structure with ROS1 G2032R, the most frequently identified ROS1 resistance mutation, reveals that zidesamtinib uniquely accommodates the mutated residue while potentially clashing with tropomyosin-related kinases, consistent with its selective ROS1-targeting design and supported by computational modeling. Taken together, these data support zidesamtinib's potential as a novel best-in-class ROS1 inhibitor. |
| Volume | 24(7) |
| Pages | 1005-1019 |
| Published | 2025-7-2 |
| DOI | 10.1158/1535-7163.MCT-25-0025 |
| PII | 762062 |
| PMID | 40299789 |
| PMC | PMC12214885 |
| MeSH | Animals Brain Neoplasms / drug therapy Brain Neoplasms / genetics Cell Line, Tumor Drug Resistance, Neoplasm* / drug effects Drug Resistance, Neoplasm* / genetics Humans Mice Mutation* Protein Kinase Inhibitors* / chemistry Protein Kinase Inhibitors* / pharmacology Protein-Tyrosine Kinases* / antagonists & inhibitors Protein-Tyrosine Kinases* / chemistry Protein-Tyrosine Kinases* / genetics Proto-Oncogene Proteins* / antagonists & inhibitors Proto-Oncogene Proteins* / chemistry Proto-Oncogene Proteins* / genetics Xenograft Model Antitumor Assays |
| IF | 5.615 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | News |
| Total number of mentions | 23 |
| Altmetric score changes over past 6months | 5.0 |
| Resource | |
| Human and Animal Cells | Ba/F3(RCB0805) |