PMID- 27613526 OWN - NLM STAT- MEDLINE DCOM- 20171113 LR - 20190221 IS - 1556-1380 (Electronic) IS - 1556-0864 (Print) IS - 1556-0864 (Linking) VI - 11 IP - 12 DP - 2016 Dec TI - An Anaplastic Lymphoma Kinase Immunohistochemistry-Negative but Fluorescence In Situ Hybridization-Positive Lung Adenocarcinoma Is Resistant to Crizotinib. PG - 2248-2252 LID - S1556-0864(16)30924-8 [pii] LID - 10.1016/j.jtho.2016.08.139 [doi] AB - INTRODUCTION: Oncogenic fusion of anaplastic lymphoma kinase (ALK) with echinoderm microtubule associated protein like 4 protein or other partner genes occurs in 3% to 6% of lung adenocarcinomas. Although fluorescence in situ hybridization (FISH) is the accepted standard for detecting anaplastic lymphoma receptor tyrosine kinase gene (ALK) gene rearrangement that gives rise to new fusion genes, not all ALK FISH-positive patients respond to ALK inhibitor therapies. We report here an ALK FISH-positive patient-derived xenograft (PDX) that was nonresponsive to crizotinib therapy. METHODS: The PDX patient human lung cancer (PHLC402) was established in NOD/SCID mice from a patient with resected pT4N1M0 lung adenocarcinoma. ALK gene status was investigated using the standard FISH break-apart assay, reverse-transcriptase quantitative polymerase chain reaction, RNA sequencing and immunohistochemical assay using the 5A4 antibody. PHLC402 was treated with crizotinib (50 mg/kg) by daily oral gavage. RESULTS: ALK FISH assay was positive in both the primary patient tumor and PDX, which were negative for ALK protein expression by immunohistochemical analysis. ALK fusion product was not detected by RNA sequencing and reverse-transcriptase quantitative polymerase chain reaction comparing the 5' and 3' ALK transcript levels. Crizotinib treatment of PHLC402 grown in mice resulted in no tumor response. CONCLUSION: ALK protein expression may be necessary for ALK FISH-positive lung cancer to be responsive to ALK inhibitor therapy. CI - Copyright (c) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. FAU - Shi, Ruoshi AU - Shi R AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. FAU - Varella-Garcia, Marileila AU - Varella-Garcia M AD - Division of Medical Oncology, University of Colorado Denver, Denver, Colorado. FAU - Li, Ming AU - Li M AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada. FAU - Ludkovski, Olga AU - Ludkovski O AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada. FAU - Danesh, Arnavaz AU - Danesh A AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada. FAU - Ng, Christine AU - Ng C AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada. FAU - Pham, Nhu-An AU - Pham NA AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada. FAU - Pugh, Trevor AU - Pugh T AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. FAU - Shepherd, Frances A AU - Shepherd FA AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Tsao, Ming-Sound AU - Tsao MS AD - University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: Ming.Tsao@uhn.ca. LA - eng GR - P30 CA046934/CA/NCI NIH HHS/United States PT - Case Reports PT - Journal Article DEP - 20160906 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Pyridines) RN - 53AH36668S (Crizotinib) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Alk protein, mouse) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Adenocarcinoma/*genetics/pathology MH - Adenocarcinoma of Lung MH - Anaplastic Lymphoma Kinase MH - Crizotinib MH - Humans MH - Immunohistochemistry/*methods MH - In Situ Hybridization, Fluorescence/*methods MH - Lung Neoplasms/*genetics/pathology MH - Male MH - Middle Aged MH - Protein Kinase Inhibitors/administration & dosage/pharmacology/*therapeutic use MH - Pyrazoles/administration & dosage/pharmacology/*therapeutic use MH - Pyridines/administration & dosage/pharmacology/*therapeutic use MH - Receptor Protein-Tyrosine Kinases/*immunology PMC - PMC5573599 MID - NIHMS898554 OTO - NOTNLM OT - Crizotinib OT - FISH OT - IHC OT - Lung cancer OT - Patient-derived xenograft COIS- Disclosure: The authors declare no conflict of interest related to this work. EDAT- 2016/09/11 06:00 MHDA- 2017/11/14 06:00 PMCR- 2017/08/28 CRDT- 2016/09/11 06:00 PHST- 2016/07/05 00:00 [received] PHST- 2016/08/20 00:00 [revised] PHST- 2016/08/22 00:00 [accepted] PHST- 2016/09/11 06:00 [pubmed] PHST- 2017/11/14 06:00 [medline] PHST- 2016/09/11 06:00 [entrez] PHST- 2017/08/28 00:00 [pmc-release] AID - S1556-0864(16)30924-8 [pii] AID - 10.1016/j.jtho.2016.08.139 [doi] PST - ppublish SO - J Thorac Oncol. 2016 Dec;11(12):2248-2252. doi: 10.1016/j.jtho.2016.08.139. Epub 2016 Sep 6.