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

Oncologist. 2025 Jan 17;30(1):oyae143. doi: 10.1093/oncolo/oyae143.

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.

Keywords: ALK inhibitors; ALK translocations; NSCLC; functional validation; molecular profiling.

Publication types

  • Case Reports

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung* / drug therapy
  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / pathology
  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use
  • Anaplastic Lymphoma Kinase* / genetics
  • Crizotinib* / pharmacology
  • Crizotinib* / therapeutic use
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Humans
  • Lactams / therapeutic use
  • Lactams, Macrocyclic / pharmacology
  • Lactams, Macrocyclic / therapeutic use
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Male
  • Middle Aged
  • Mutation
  • Mutation, Missense
  • Oncogene Proteins, Fusion / genetics
  • Organophosphorus Compounds / pharmacology
  • Organophosphorus Compounds / therapeutic use
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles* / pharmacology
  • Pyrazoles* / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Pyrimidines
  • Receptor Protein-Tyrosine Kinases / genetics

Substances

  • Anaplastic Lymphoma Kinase
  • Crizotinib
  • ALK protein, human
  • Pyrazoles
  • Protein Kinase Inhibitors
  • lorlatinib
  • brigatinib
  • Aminopyridines
  • Organophosphorus Compounds
  • Lactams
  • Lactams, Macrocyclic
  • Pyridines
  • Receptor Protein-Tyrosine Kinases
  • Oncogene Proteins, Fusion
  • EML4-ALK fusion protein, human
  • Pyrimidines