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LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion.
- Source :
-
Communications biology [Commun Biol] 2024 Apr 04; Vol. 7 (1), pp. 412. Date of Electronic Publication: 2024 Apr 04. - Publication Year :
- 2024
-
Abstract
- The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Anaplastic Lymphoma Kinase genetics
Anaplastic Lymphoma Kinase therapeutic use
Drug Resistance, Neoplasm genetics
Lactams, Macrocyclic pharmacology
Lactams, Macrocyclic therapeutic use
Mutation
Cytoskeletal Proteins genetics
Receptor Protein-Tyrosine Kinases genetics
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung genetics
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Aminopyridines
Lactams
Pyrazoles
Subjects
Details
- Language :
- English
- ISSN :
- 2399-3642
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Communications biology
- Publication Type :
- Academic Journal
- Accession number :
- 38575808
- Full Text :
- https://doi.org/10.1038/s42003-024-06116-6