Reference Detail

Ref Type

Journal Article

PMID

(38960389)

Authors

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, Witte HM

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
The oncologist			2024 Jul 03		Oncologist

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	R1181H	missense	unknown	ALK R1181H lies within the protein kinase domain of the Alk protein (UniProt.org). R1181H results in increased cytokine-independent growth and phosphorylation of Stat3, Erk, Akt, and demonstrates resistance to first generation Alk inhibitors in the context of EML4-ALK in culture (PMID: 38960389), but has not been individually characterized and therefore, its effect on Alk protein function is unknown.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK R1181H	Advanced Solid Tumor	predicted - sensitive	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited proliferation of cells expressing EML4-ALK and ALK R1181H in culture (PMID: 38960389).	38960389
EML4 - ALK ALK R1181H	lung adenocarcinoma	sensitive	Brigatinib	Case Reports/Case Series	Actionable	In a clinical case study, Alunbrig (brigatinib) treatment resulted in an ongoing partial response after 12 months in a patient with lung adenocarcinoma harboring EML4-ALK and ALK R1181H, and in a preclinical study, inhibited proliferation of cells expressing EML4-ALK and ALK R1181H in culture (PMID: 38960389).	38960389
EML4 - ALK ALK R1181H	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK R1181H was identified in the post-progression biopsy of a patient with lung adenocarcinoma harboring EML4-ALK who previously responded to treatment with Xalkori (crizotinib) (PMID: 38960389).	38960389