Molecular tumor board: molecularly adjusted therapy upon identification and functional validation of a novel ALK resistance mutation in a case of lung adenocarcinoma.

Autor:	Arndt A; Institute for Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany., Neumann C; Department of Hematology and Oncology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany., Riecke A; Department of Hematology and Oncology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany., Bauer A; Department of Hematology and Oncology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany., Müller M; Department of Hematology and Oncology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany., Wölfle-Guter M; Internistische Praxisgemeinschaft Ehingen, 89584 Ehingen, Germany., Grunert M; Department of Nuclear Medicine, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany.; Department of Nuclear Medicine, University Hospital Ulm, 89081 Ulm, Germany., Busch H; Medical Systems Biology Group, University of Lübeck, 23538 Lübeck, Germany.; Institute for Cardiogenetics, University of Lübeck, 23538 Lübeck, Germany.; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., Künstner A; Medical Systems Biology Group, University of Lübeck, 23538 Lübeck, Germany.; Institute for Cardiogenetics, University of Lübeck, 23538 Lübeck, Germany.; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., von Bubnoff N; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., Fliedner S; Institute for Cardiogenetics, University of Lübeck, 23538 Lübeck, Germany.; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., Greinert D; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., Osius J; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., Nagarathinam K; Department of Biochemistry, University of Lübeck, 23538 Lübeck, Germany., Steinestel K; Institute for Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany., Gorantla SP; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., Gebauer N; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany., Witte HM; Institute for Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany.; Department of Hematology and Oncology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany.; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany.
Jazyk:	angličtina
Zdroj:	The oncologist [Oncologist] 2024 Jul 03. Date of Electronic Publication: 2024 Jul 03.
DOI:	10.1093/oncolo/oyae143
Abstrakt:	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.)
Databáze:	MEDLINE
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