title: Expanded Circulating Tumor Cells from a Patient with ALK-Positive Lung Cancer Present with EML4-ALK Rearrangement Along with Resistance Mutation and Enable Drug Sensitivity Testing: A Case Study.
abstract: The emergence of liquid biopsy using circulating tumor cells (CTCs) as a resource to identify genomic alterations in cancer presents new opportunities for diagnosis, therapy, and surveillance. We identified EML4-ALK gene rearrangement in expanded CTCs from a patient with ALK-positive lung adenocarcinoma. At the time of radiographic progression, CTCs obtained from the patient revealed a drug resistance mutation (i.e., L1196M on the ALK gene). CTCs were expanded ex vivo and drug sensitivity testing was performed using two ALK inhibitors, crizotinib and ceritinib. The half maximal inhibitory concentration of ceritinib was 1664 nM compared with crizotinib (2268 nM), showing that ceritinib was a more potent ALK inhibitor. We show that it is feasible to detect serial genetic alterations in expanded CTCs and perform in vitro drug screening. These findings support the clinical utility of CTCs not only for diagnosis, but also a potential tool for drug sensitivity testing in distinct subsets of lung cancer and for personalized precision medicine.
authors: Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
authors: Zhuo
authors: Z
authors: Zhang
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors: Hiroe
authors: H
authors: Shiratsuchi
authors: Department of Urology, Henry Ford Health System, Detroit, Michigan.
authors: Nallasivam
authors: N
authors: Palanisamy
authors: Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan; Translational Oncology Program, University of Michigan, Ann Arbor, Michigan. Electronic address: snagrath@umich.edu.
authors: Sunitha
authors: S
authors: Nagrath
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Veterans Administration Ann Arbor Healthcare System, Ann Arbor, Michigan.
authors: Nithya
authors: N
authors: Ramnath
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: EML4-ALK; Expanded CTCs; L1196M; Liquid biopsy; NSCLC