title: Rare Complex Mutational Profile in an ALK Inhibitor-resistant Non-small Cell Lung Cancer.
abstract: Testing for somatic alterations, including anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and epidermal growth factor receptor gene (EGFR) mutations, is standard practice in the diagnostic evaluation and therapeutic management of non-small cell lung cancer (NSCLC), where the results of such tests can predict response to targeted-therapy. ALK rearrangements, EGFR mutations and mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) are considered mutually exclusive in NSCLC. Herein we identified a KRAS Q22K mutation and frameshift mutations in the genes encoding serine/threonine kinase 11 (STK11) and ataxia telangiectasia mutated serine/threonine kinase (ATM) by next-generation sequencing in a patient with ALK rearrangement-positive oligo-metastatic NSCLC, whose disease progressed while on two ALK-targeted therapies. Such a complex diagnostic genetic profile has not been reported in ALK fusion-positive NSCLC. This case highlights the utility of comprehensive molecular testing in the diagnosis of NSCLC.
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A. Elizabeth.Azzato@uphs.upenn.edu elizabeth.azzato@gmail.com.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Azzato
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Charuhas
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Vania
authors.initials: V
authors.lastname: Aikawa
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Charu
authors.initials: C
authors.lastname: Aggarwal
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Evan
authors.initials: E
authors.lastname: Alley
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Jacobs
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Morrissette
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Robert
authors.initials: R
authors.lastname: Daber
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D015321:Gene Rearrangement; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: ALK inhibitor; ALK translocation; ATM; KRAS; Non-small cell lung cancer; STK11; case report; crizotinib resistance; genomics; next-generation sequencing