1. Molecular tumor board: molecularly adjusted therapy upon identification and functional validation of a novel ALK resistance mutation in a case of lung adenocarcinoma.
- Author
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Arndt A, Neumann C, Riecke A, Bauer A, Müller M, Wölfle-Guter M, Grunert M, Busch H, Künstner A, von Bubnoff N, Fliedner S, Greinert D, Osius J, Nagarathinam K, Steinestel K, Gorantla SP, Gebauer N, and Witte HM
- Subjects
- Humans, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Aminopyridines therapeutic use, Aminopyridines pharmacology, Organophosphorus Compounds therapeutic use, Organophosphorus Compounds pharmacology, Lactams therapeutic use, Mutation, Lactams, Macrocyclic therapeutic use, Lactams, Macrocyclic pharmacology, Adenocarcinoma genetics, Adenocarcinoma drug therapy, Adenocarcinoma pathology, Male, Mutation, Missense, Female, Pyridines therapeutic use, Pyridines pharmacology, Receptor Protein-Tyrosine Kinases genetics, Oncogene Proteins, Fusion genetics, Middle Aged, Pyrimidines, Anaplastic Lymphoma Kinase genetics, Crizotinib therapeutic use, Crizotinib pharmacology, Drug Resistance, Neoplasm genetics, Lung Neoplasms genetics, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung pathology, Pyrazoles therapeutic use, Pyrazoles pharmacology
- Abstract
We report a case of a long-term surviving patient with EML4/ALK translocated non-small cell adenocarcinoma of the lung in UICC8 stage IVA. During recurrence under continuous crizotinib therapy, a hitherto insufficiently characterized missense mutation in the ALK gene (Arg1181His) was identified through targeted sequencing. The aforementioned EML4/ALK translocation could still be detected in this situation. Employing a 3D reconstruction of the ALK tertiary structure, considering its interaction with various ALK inhibitors at the molecular binding site, our analysis indicated the presence of a mutation associated with crizotinib resistance. To validate the biological relevance of this previously unknown mutation, we carried out an in vitro validation approach in cell culture in addition to the molecular diagnostics accompanied by the molecular tumor board. The tumor scenario was mimicked through retroviral transfection. Our comparative in vitro treatment regimen paired with the clinical trajectory of the patient, corroborated our initial clinical and biochemical suspicions. Our approach demonstrates preclinical, in silico, and clinical evidence of a novel crizotinib resistance mutation in ALK as well as sensitivity toward brigatinib and potentially lorlatinib. In future cases, this procedure represents an important contribution to functional diagnostics in the context of molecular tumor boards., (© The Author(s) 2024. Published by Oxford University Press.)
- Published
- 2025
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