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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