DOCSLIB.ORG

Genomic Aberrations Associated with Erlotinib Resistance in Non-Small Cell Lung Cancer Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genomic Aberrations Associated with Erlotinib Resistance in Non-Small Cell Lung Cancer Cells ANTICANCER RESEARCH 33: 5223-5234 (2013) Genomic Aberrations Associated with Erlotinib Resistance in Non-small Cell Lung Cancer Cells MASAKUNI SERIZAWA1, TOSHIAKI TAKAHASHI2, NOBUYUKI YAMAMOTO2,3 and YASUHIRO KOH1 1Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, Japan; 2Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan; 3Third Department of Internal Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan Abstract. Background/Aim: Mechanisms of resistance to mutations develop resistance, usually within one year of epidermal growth factor receptor (EGFR)-tyrosine kinase treatment. Therefore, there is an urgent need to elucidate the inhibitors (TKIs) in non-small cell lung cancer (NSCLC) underlying mechanisms of resistance in such tumors to are not fully-understood. In this study we aimed to overcome this obstacle (11-14, 17, 24). Recent studies elucidate remaining unknown mechanisms using erlotinib- suggest that mechanisms of acquired resistance to EGFR- resistant NSCLC cells. Materials and Methods: We TKIs can be categorized into three groups: occurrence of performed array comparative genomic hybridization genetic alterations, activation of downstream pathways via (aCGH) to identify genomic aberrations associated with bypass signaling, and phenotypic transformation (15, 16, 21); EGFR-TKI resistance in erlotinib-resistant PC-9ER cells. therapeutic strategies to overcome these resistance Real-time polymerase chain reaction (PCR) and mechanisms are under development. However, although the immunoblot analyses were performed to confirm the results causes of acquired resistance to EGFR-TKIs have been of aCGH. Results: Among the five regions with copy investigated, in more than 30% of patients with acquired number gain detected in PC-9ER cells, we focused on resistance to EGFR-TKI treatment, the mechanisms remain 22q11.2-q12.1 including v-crk avian sarcoma virus CT10 unknown (15). We previously reported that erlotinib-resistant oncogene homolog-like (CRKL), the overexpression of PC-9ER cells, established from PC-9 NSCLC cells with an which seemed to be associated with EGFR-TKI resistance. EGFR-activating mutation, manifest enhanced cell motility Blockade of downstream phosphatidylinositol 3-kinase which can be abolished by the blockade of transforming (PI3K)/v-akt murine thymoma viral oncogene homolog growth factor-β (TGF-β)/SMAD family member-2 (SMAD2) (AKT) signaling using NVP-BEZ235 suppressed the pathway (18). At the same time, constitutive activation of proliferation of PC-9ER cells, implying the involvement of phosphatidylinositol 3–kinase (PI3K)/v-akt murine thymoma acquired CRKL amplification in EGFR-TKI resistance. viral oncogene homolog (AKT) signaling in PC-9ER cells Conclusion: Acquired CRKL amplification was identified as was observed and this might confer resistance to EGFR- contributing to EGFR-TKI resistance; this cell line model TKIs. However, the mechanism responsible for this activated can be utilized to study this resistance mechanism. signaling on the genetic level remains unclear. Array comparative genomic hybridization (aCGH) Despite a dramatic initial response to the epidermal growth analysis is a high-resolution, genome-wide screening factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) technology that allows for rapid survey of genomic gefitinib and erlotinib, the majority of patients with non- instability, especially of copy number alterations, which are small cell lung cancer (NSCLC) with EGFR-activating key genetic aberrations relevant to the development and progression of human cancers (20). Moreover, aCGH analysis is useful as a means to explore mechanisms of resistance to EGFR-TKIs. For example, met proto-oncogene Correspondence to: Yasuhiro Koh, MD, Drug Discovery and (MET) amplification, a major cause of resistance to EGFR- Development Division, Shizuoka Cancer Center Research Institute, TKIs was detected in gefitinib-resistant NSCLC by aCGH 1007 Shimonagakubo Nagaizumi-cho Sunto-gun, Shizuoka, 411- analysis (4). 8777, Japan. Tel: +81 559895222, Fax: +81 559896085, e-mail: [email protected] In the present study, we aimed to clarify genomic aberrations, especially copy number alterations, relevant to Key Words: EGFR-TKI resistance, erlotinib, amplification, copy- EGFR-TKI resistance mechanisms in PC-9ER cells using number alteration, CRKL, non-small cell lung cancer. aCGH analysis. 0250-7005/2013 $2.00+.40 5223 ANTICANCER RESEARCH 33: 5223-5234 (2013) Table I. Chromosome aberrations in PC-9ER1 cells. Chr Cytoband Start End Overlap Number of Log2 Log2 Number of Genes (hg19) (hg19) detected in aCGH probes ratio ratio genes included in PC-9ER1 included (amplifi- (deletion) included in chromosome and in genomic cation) chromosome aberration PC-9ER4 aberration aberration 1 p35.2- 31,964,879 32,473,479 l 204 –1.07 8 LOC284551, TINAGL1, HCRTR1, PEF1, p35.1 COL16A1, BAI2, SPOCD1, PTP4A2 1 p31.1 72,341,387 72,544,038 104 –1.10 1 NEGR1 2 q14.2- 120,609,630 122,530,342 l 724 1.09 12 PTPN4, EPB41L5, TMEM185B, RALB, q14.3 INHBB, LOC84931, GLI2, TFCP2L1, CLASP1, RNU4ATAC, MKI67IP, TSN 2 q22.2 142,338,612 142,570,218 115 –1.47 1 LRP1B 3 p14.2 60,070,343 60,113,818 l 23 –2.73 1 FHIT 3 p14.2 60,196,167 60,329,532 l 63 –2.83 1 FHIT 3 p14.2 60,344,382 60,375,603 l 18 –3.33 1 FHIT 3 p14.2 60,536,419 60,603,993 l 33 2.46 1 FHIT 3 p14.2 62,479,806 62,541,800 l 33 –1.55 1 CADPS 3 p13 71,345,692 71,395,229 l 27 –1.50 1 FOXP1 8 q24.12- 119,739,051 130,277,369 l 3,329 1.56 45 TNFRSF11B, COLEC10, MAL2, NOV, q24.21 ENPP2, TAF2, DSCC1, DEPDC6, COL14A1, MRPL13, MTBP, SNTB1, HAS2, HAS2AS, ZHX2, DERL1, WDR67, FAM83A, LOC100131726, C8orf76, ZHX1, ATAD2, WDYHV1, FBXO32, KLHL38, ANXA13, FAM91A1, FER1L6, TMEM65, TRMT12, RNF139, TATDN1, NDUFB9, MTSS1, LOC157381, ZNF572, SQLE, KIAA0196, NSMCE2, TRIB1, FAM84B, POU5F1B, LOC727677, MYC, PVT1 8 q24.23 136,467,502 136,771,745 l 120 1.24 1 KHDRBS3 10 p13-p11.1 16,013,438 38,629,589 l 7,704 –1.01 90 PTER, C1QL3, RSU1, CUBN, TRDMT1, VIM, ST8SIA6, PTPLA, STAM, FAM23A, MRC1, MRC1L1, SLC39A12, CACNB2, NSUN6, ARL5B, PLXDC2, NEBL, C10orf113, C10orf114, C10orf140, MLLT10, DNAJC1, COMMD3, BMI1, SPAG6, PIP4K2A, ARMC3, MSRB2, PTF1A, C10orf67, OTUD1, KIAA1217, PRINS, ARHGAP21, PRTFDC1, ENKUR, THNSL1, LOC100128811, GPR158, MYO3A, GAD2, APBB1IP, C10orf50, LOC731789, PDSS1, ABI1, NCRNA00202, ANKRD26, YME1L1, MASTL, ACBD5, LOC387646, PTCHD3, RAB18, MKX, ARMC4, MPP7, WAC, BAMBI, LYZL1, LOC387647, SVIL, KIAA1462, MTPAP, LOC729668, MAP3K8, LYZL2, ZNF438, LOC220930, ZEB1, ARHGAP12, KIF5B, EPC1, CCDC7, C10orf68, ITGB1, NRP1, PARD3, CUL2, CREM, CCNY, GJD4, FZD8, ANKRD30A, ZNF248, ZNF25, ZNF33A, ZNF37A, LOC100129055 13 q31.3 94,063,273 94,377,155 l 163 –2.82 1 GPC6 15 q22.2 60,661,598 60,713,059 l 32 –1.43 2 ANXA2, NARG2 19 q13.11 34,965,663 34,992,122 16 –1.01 1 WTIP 22 q11.21- 20,889,601 29,555,904 l 4,243 1.16 108 MED15, POM121L4P, TMEM191A, q12.1 PI4KA, SERPIND1, SNAP29, CRKL, AIFM3, LZTR1, THAP7, FLJ39582, MGC16703, P2RX6, SLC7A4, P2RX6P, Table I. Continued 5224 Serizawa et al: Genomic Aberrations Associated with EGFR-TKI Resistance in NSCLC Table I. Continued Chr Cytoband Start End Overlap Number of Log2 Log2 Number of Genes (hg19) (hg19) detected in aCGH probes ratio ratio genes included in PC-9ER1 included (amplifi- (deletion) included in chromosome and in genomic cation) chromosome aberration PC-9ER4 aberration aberration LOC400891, POM121L8P, RIMBP3C, RIMBP3B, HIC2, PI4KAP2, UBE2L3, YDJC, CCDC116, SDF2L1, PPIL2, YPEL1, MAPK1, PPM1F, TOP3B, VPREB1, LOC96610, ZNF280B, ZNF280A, PRAME, LOC648691, POM121L1P, GGTLC2, RTDR1, GNAZ, RAB36, BCR, ZDHHC8P, IGLL1, C22orf43, LOC91316, RGL4, ZNF70, VPREB3, C22orf15, CHCHD10, MMP11, SMARCB1, DERL3, SLC2A11, MIF, GSTT2, DDTL, DDT, GSTTP1, LOC391322, GSTT1, GSTTP2, CABIN1, SUSD2, GGT5, POM121L9P, CYTSA, ADORA2A, C22orf45, UPB1, C22orf13, SNRPD3, GGT1, C22orf36, LOC644165, POM121L10P, PIWIL3, TOP1P2, SGSM1, TMEM211, KIAA1671, CRYBB3, CRYBB2, IGLL3, LRP5L, ADRBK2, MYO18B, SEZ6L, ASPHD2, HPS4, SRRD, TFIP11, TPST2, CRYBB1, CRYBA4, MIAT, MN1, PITPNB, LOC284900, TTC28, CHEK2, HSCB, CCDC117, XBP1, ZNRF3, C22orf31, KREMEN1 22 q12.1- 29,560,131 30,165,998 l 312 –1.28 17 KREMEN1, EMID1, RHBDD3, q12.2 EWSR1, GAS2L1, RASL10A, AP1B1, SNORD125, RFPL1S, RFPL1, NEFH, THOC5, NIPSNAP1, NF2, CABP7, ZMAT5, UCRC Materials and Methods aCGH experiments and data analysis. aCGH analysis was performed with 500 ng genomic DNA from PC-9 cells (reference), and PC-9ER1 Cell culture and reagents. The human lung adenocarcinoma cell or PC-9ER4 cells (experimental sample) using SurePrint G3 Human line PC-9 harboring an EGFR-activating mutation (E746-A750del CGH 1×1M Oligo Microarrays (Agilent Technologies, Palo Alto, CA, at exon 19) was provided by Dr. Fumiaki Koizumi (National USA) according to standard procedures. Genomic Workbench Cancer Center Hospital, Tokyo, Japan). Erlotinib-resistant PC-9ER software ver. 7.0.4.0 (Agilent Technologies) was used to identify cells (PC-9ER1 and PC-9ER4) were established from PC-9 cells consecutive genomic aberrations using the statistical algorithm ADM- as previously reported (18). All the cell lines used in this study 2 with a sensitivity threshold of 10.0, and genomic aberration filters were maintained in RPMI-1640 (Invitrogen, Carlsbad, CA, USA) (absolute average of log2 ratios of 1.0 in more than10 consecutive supplemented with 10% heat-inactivated fetal bovine serum (FBS; probes). Gene annotation enrichment analysis of genes involved in regions of genomic aberration was performed with The Database for Invitrogen) in humidified air containing 5% CO2 at 37˚C. Erlotinib and NVP-BEZ235 were purchased from LC laboratories (Woburn, Annotation, Visualization and Integrated Discovery (DAVID) MA, USA). Bioinformatics Resources 6.7 (http://david.abcc.ncifcrf.gov/) (6, 7). The acceptable statistical significance level of the gene annotation Nucleic acid sample preparation. Genomic DNA of PC-9 and PC- enrichment analysis was set at a p-value of lower than 0.1. 9ER cells was extracted using the QIAamp DNA mini kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions.
Load more

Recommended publications
  • BLOC-1 and BLOC-3 Regulate VAMP7 Cycling to and From
    BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers Megan K. Dennis1,2, Cédric Delevoye3,4, Amanda Acosta-Ruiz1,2, Ilse Hurbain3,4, Maryse Romao3,4, Geoffrey G. Hesketh5, Philip S. Goff6, Elena V. Sviderskaya6, Dorothy C. Bennett6, J. Paul Luzio5, Thierry Galli7, David J. Owen5, Graça Raposo3,4 and Michael S. Marks1,2,8 1Dept. of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, and 2Dept. of Pathology and Laboratory Medicine and Dept of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, F-75005, Paris, France; 4 Institut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), F-75005, Paris, France; 5Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK; 6Cell Biology & Genetics Research Centre, St. George’s , University of London, London, UK; 7Sorbonne Paris-Cité, Univ. Paris-Diderot, Institut Jacques Monod, CNRS UMR7592, INSERM ERL U950, Membrane Traffic in Health & Disease, Paris, France. 8To whom correspondence should be addressed: Michael S. Marks, Ph.D. Dept. of Pathology & Laboratory Medicine Children's Hospital of Philadelphia Research Institute 816G Abramson Research Center 3615 Civic Center Blvd. Philadelphia, PA 19104 Tel: 215-590-3664 Email: [email protected] Running title: VAMP7 into and out of melanosomes Keywords: SNARE, lysosome-related organelle, melanogenesis, Hermansky-Pudlak syndrome, recycling, endosome, 2 ABSTRACT Endomembrane organelle maturation requires cargo delivery via fusion with membrane transport intermediates and recycling of fusion factors to their sites of origin.
    [Show full text]
  • Diagnosing Platelet Secretion Disorders: Examples Cases
    Diagnosing platelet secretion disorders: examples cases Martina Daly Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Disclosures for Martina Daly In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Consultant No relevant conflicts of interest to declare Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory No relevant conflicts of interest to declare Board Platelet granule release Agonists (FIIa, Collagen, ADP) Signals Activation Shape change Membrane fusion Release of granule contents Platelet storage organelles lysosomes a granules Enzymes including cathepsins Adhesive proteins acid hydrolases Clotting factors and their inhibitors Fibrinolytic factors and their inhibitors Proteases and antiproteases Growth and mitogenic factors Chemokines, cytokines Anti-microbial proteins Membrane glycoproteins dense (d) granules ADP/ATP Serotonin histamine inorganic polyphosphate Platelet a-granule contents Type Prominent components Membrane glycoproteins GPIb, aIIbb3, GPVI Clotting factors VWF, FV, FXI, FII, Fibrinogen, HMWK, FXIII? Clotting inhibitors TFPI, protein S, protease nexin-2 Fibrinolysis components PAI-1, TAFI, a2-antiplasmin, plasminogen, uPA Other protease inhibitors a1-antitrypsin, a2-macroglobulin
    [Show full text]
  • TARCEVA for Severe Renal These Highlights Do Not Include All the Information Needed to Use Toxicity
    HIGHLIGHTS OF PRESCRIBING INFORMATION patients at risk of dehydration. Withhold TARCEVA for severe renal These highlights do not include all the information needed to use toxicity. (5.2) TARCEVA® safely and effectively. See full prescribing information for • Hepatotoxicity: Occurs with or without hepatic impairment, including TARCEVA. hepatic failure and hepatorenal syndrome: Monitor periodic liver testing. Withhold or discontinue TARCEVA for severe or worsening liver tests. (5.3) TARCEVA (erlotinib) tablets, for oral use • Gastrointestinal perforations: Discontinue TARCEVA. (5.4) Initial U.S. Approval: 2004 • Bullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5) • ---------------------------RECENT MAJOR CHANGES--------------------------­ Cerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. (5.6) Indications and Usage, Non-Small Cell Lung Cancer (NSCLC) (1.1) 10/2016 • Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is Dosage and Administration (2.1) 06/2016 increased in patients with pancreatic cancer. (5.7) Dosage and Administration, Dose Modifications (2.4) 05/2016 • Ocular disorders: Discontinue TARCEVA for corneal perforation, Warnings and Precautions, Cerebrovascular Accident (5.6) 10/2016 ulceration or persistent severe keratitis. (5.8) Warnings and Precautions, Embryo-fetal Toxicity (5.10) 10/2016 • Hemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. (5.9) ---------------------------INDICATIONS
    [Show full text]
  • A Network of Bhlhzip Transcription Factors in Melanoma: Interactions of MITF, TFEB and TFE3
    A network of bHLHZip transcription factors in melanoma: Interactions of MITF, TFEB and TFE3 Josué A. Ballesteros Álvarez Thesis for the degree of Philosophiae Doctor January 2019 Net bHLHZip umritunarþátta í sortuæxlum: Samstarf milli MITF, TFEB og TFE3 Josué A. Ballesteros Álvarez Ritgerð til doktorsgráðu Leiðbeinandi/leiðbeinendur: Eiríkur Steingrímsson Doktorsnefnd: Margrét H. Ögmundsdóttir Þórarinn Guðjónsson Jórunn E. Eyfjörð Lars Rönnstrand Janúar 2019 Thesis for a doctoral degree at tHe University of Iceland. All rigHts reserved. No Part of tHis Publication may be reProduced in any form witHout tHe Prior permission of the copyright holder. © Josue A. Ballesteros Álvarez. 2019 ISBN 978-9935-9421-4-2 Printing by HáskólaPrent Reykjavik, Iceland 2019 Ágrip StjórnPróteinin MITF , TFEB, TFE3 og TFEC (stundum nefnd MiT-TFE þættirnir) tilheyra bHLHZip fjölskyldu umritunarþátta sem bindast DNA og stjórna tjáningu gena. MITF er mikilvægt fyrir myndun og starfsemi litfruma en ættingjar þess, TFEB og TFE3, stjórna myndun og starfsemi lysósóma og sjálfsáti. Sjálfsát er líffræðilegt ferli sem gegnir mikilvægu hlutverki í starfsemi fruma en getur einnig haft áHrif á myndun og meðHöndlun sjúkdóma. Í verkefni þessu var samstarf MITF, TFE3 og TFEB Próteinanna skoðað í sortuæxlisfrumum og hvaða áhrif þau Hafa á tjáningu hvers annars. Eins og MITF eru TFEB og TFE3 genin tjáð í sortuæxlisfrumum og sortuæxlum; TFEC er ekki tjáð í þessum frumum og var því ekki skoðað í þessu verkefni. Með notkun sérvirkra hindra var sýnt að boðleiðir hafa áhrif á staðsetningu próteinanna þriggja í sortuæxlisfrumum. Umritunarþættir þessir geta bundist skyldum DNA-bindisetum og haft áhrif á tjáningu gena sem eru nauðsynleg fyrir myndun bæði lýsósóma og melanósóma.
    [Show full text]
  • Partial Response to Erlotinib in a Patient with Imatinib-Refractory
    Verma et al. Clin Sarcoma Res (2020) 10:28 https://doi.org/10.1186/s13569-020-00149-1 Clinical Sarcoma Research CASE REPORT Open Access Partial response to erlotinib in a patient with imatinib-refractory sacral chordoma Saurav Verma1, Surya Prakash Vadlamani1, Shamim Ahmed Shamim2, Adarsh Barwad3, Sameer Rastogi4* and S. T. Arun Raj2 Abstract Background: Chordoma is a rare, slow growing and locally aggressive mesenchymal neoplasm with uncommon distant metastases. It is a chemo-resistant disease with surgery and radiotherapy being the mainstay in treatment of localized disease. In advanced disease imatinib has a role. We report a case of metastatic sacral chordoma with symp- tomatic and radiological response to erlotinib post-progression on imatinib. Case presentation: A 48-year-old male with a sacral chordoma underwent partial sacrectomy followed by post- operative radiotherapy. Upon recurrence he received palliative radiotherapy to hemipelvis and was ofered therapy with imatinib. However, the disease was refractory to imatinib and he was started on treatment with erlotinib—show- ing a partial response on imaging at two months. He is currently doing well at 13 months since start of erlotinib. Conclusions: As seen in previously reported cases, erlotinib is a therapeutic option in advanced chordoma, even in imatinib refractory cases and thus warrants exploration of its therapeutic role in prospective clinical trials. Keywords: Chordoma, EGFR, Erlotinib Background adjuvant setting after a full or subtotal resection, and as Chordoma is a rare mesenchymal neoplasm which arises the primary treatment in unresectable disease. from the remnants of primitive notochord [1]. It accounts Chordoma responds poorly to cytotoxic chemotherapy.
    [Show full text]
  • Supplementary Tables
    Supplementary Tables Supplementary Table S1: Preselected miRNAs used in feature selection Univariate Cox proportional hazards regression analysis of the endpoint freedom from recurrence in the training set (DKTK-ROG sample) allowed the pre-selection of 524 miRNAs (P< 0.5), which were used in the feature selection. P-value was derived from log-rank test. miRNA p-value miRNA p-value miRNA p-value miRNA p-value hsa-let-7g-3p 0.0001520 hsa-miR-1304-3p 0.0490161 hsa-miR-7108-5p 0.1263245 hsa-miR-6865-5p 0.2073121 hsa-miR-6825-3p 0.0004257 hsa-miR-4298 0.0506194 hsa-miR-4453 0.1270967 hsa-miR-6893-5p 0.2120664 hsa-miR-668-3p 0.0005188 hsa-miR-484 0.0518625 hsa-miR-200a-5p 0.1276345 hsa-miR-25-3p 0.2123829 hsa-miR-3622b-3p 0.0005885 hsa-miR-6851-3p 0.0531446 hsa-miR-6090 0.1278692 hsa-miR-3189-5p 0.2136060 hsa-miR-6885-3p 0.0006452 hsa-miR-1276 0.0557418 hsa-miR-148b-3p 0.1279811 hsa-miR-6073 0.2139702 hsa-miR-6875-3p 0.0008188 hsa-miR-3173-3p 0.0559962 hsa-miR-4425 0.1288330 hsa-miR-765 0.2141536 hsa-miR-487b-5p 0.0011381 hsa-miR-650 0.0564616 hsa-miR-6798-3p 0.1293342 hsa-miR-338-5p 0.2153079 hsa-miR-210-5p 0.0012316 hsa-miR-6133 0.0571407 hsa-miR-4472 0.1300006 hsa-miR-6806-5p 0.2173515 hsa-miR-1470 0.0012822 hsa-miR-4701-5p 0.0571720 hsa-miR-4465 0.1304841 hsa-miR-98-5p 0.2184947 hsa-miR-6890-3p 0.0016539 hsa-miR-202-3p 0.0575741 hsa-miR-514b-5p 0.1308790 hsa-miR-500a-3p 0.2185577 hsa-miR-6511b-3p 0.0017165 hsa-miR-4733-5p 0.0616138 hsa-miR-378c 0.1317442 hsa-miR-4515 0.2187539 hsa-miR-7109-3p 0.0021381 hsa-miR-595 0.0629350 hsa-miR-3121-3p
    [Show full text]
  • AP1B1 Rabbit Polyclonal Antibody – TA323221 | Origene
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TA323221 AP1B1 Rabbit Polyclonal Antibody Product data: Product Type: Primary Antibodies Applications: IHC Recommended Dilution: ELISA: 1:1000-5000, IHC: 1:25-100 Reactivity: Human, Mouse, Rat Host: Rabbit Isotype: IgG Clonality: Polyclonal Immunogen: Synthetic peptide corresponding to a region derived from 18-30 amino acids of Human Adapter-related protein complex 1 subunit beta-1 Formulation: PBS pH7.3, 0.05% NaN3, 50% glycerol Concentration: lot specific Purification: Antigen affinity purification Conjugation: Unconjugated Storage: Store at -20°C as received. Stability: Stable for 12 months from date of receipt. Gene Name: adaptor related protein complex 1 beta 1 subunit Database Link: NP_001118 Entrez Gene 11764 MouseEntrez Gene 29663 RatEntrez Gene 162 Human Q10567 Background: Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex; where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large; one medium; and one small adaptin subunit. The protein encoded by this gene serves as one of the large subunits of this complex and is a member of the adaptin protein family. This gene is a candidate meningioma gene. Alternative splicing results in multiple transcript variants. Synonyms: ADTB1; AP105A; BAM22; CLAPB2 Protein Pathways: Lysosome This product is to be used for laboratory only.
    [Show full text]
  • NICU Gene List Generator.Xlsx
    Neonatal Crisis Sequencing Panel Gene List Genes: A2ML1 - B3GLCT A2ML1 ADAMTS9 ALG1 ARHGEF15 AAAS ADAMTSL2 ALG11 ARHGEF9 AARS1 ADAR ALG12 ARID1A AARS2 ADARB1 ALG13 ARID1B ABAT ADCY6 ALG14 ARID2 ABCA12 ADD3 ALG2 ARL13B ABCA3 ADGRG1 ALG3 ARL6 ABCA4 ADGRV1 ALG6 ARMC9 ABCB11 ADK ALG8 ARPC1B ABCB4 ADNP ALG9 ARSA ABCC6 ADPRS ALK ARSL ABCC8 ADSL ALMS1 ARX ABCC9 AEBP1 ALOX12B ASAH1 ABCD1 AFF3 ALOXE3 ASCC1 ABCD3 AFF4 ALPK3 ASH1L ABCD4 AFG3L2 ALPL ASL ABHD5 AGA ALS2 ASNS ACAD8 AGK ALX3 ASPA ACAD9 AGL ALX4 ASPM ACADM AGPS AMELX ASS1 ACADS AGRN AMER1 ASXL1 ACADSB AGT AMH ASXL3 ACADVL AGTPBP1 AMHR2 ATAD1 ACAN AGTR1 AMN ATL1 ACAT1 AGXT AMPD2 ATM ACE AHCY AMT ATP1A1 ACO2 AHDC1 ANK1 ATP1A2 ACOX1 AHI1 ANK2 ATP1A3 ACP5 AIFM1 ANKH ATP2A1 ACSF3 AIMP1 ANKLE2 ATP5F1A ACTA1 AIMP2 ANKRD11 ATP5F1D ACTA2 AIRE ANKRD26 ATP5F1E ACTB AKAP9 ANTXR2 ATP6V0A2 ACTC1 AKR1D1 AP1S2 ATP6V1B1 ACTG1 AKT2 AP2S1 ATP7A ACTG2 AKT3 AP3B1 ATP8A2 ACTL6B ALAS2 AP3B2 ATP8B1 ACTN1 ALB AP4B1 ATPAF2 ACTN2 ALDH18A1 AP4M1 ATR ACTN4 ALDH1A3 AP4S1 ATRX ACVR1 ALDH3A2 APC AUH ACVRL1 ALDH4A1 APTX AVPR2 ACY1 ALDH5A1 AR B3GALNT2 ADA ALDH6A1 ARFGEF2 B3GALT6 ADAMTS13 ALDH7A1 ARG1 B3GAT3 ADAMTS2 ALDOB ARHGAP31 B3GLCT Updated: 03/15/2021; v.3.6 1 Neonatal Crisis Sequencing Panel Gene List Genes: B4GALT1 - COL11A2 B4GALT1 C1QBP CD3G CHKB B4GALT7 C3 CD40LG CHMP1A B4GAT1 CA2 CD59 CHRNA1 B9D1 CA5A CD70 CHRNB1 B9D2 CACNA1A CD96 CHRND BAAT CACNA1C CDAN1 CHRNE BBIP1 CACNA1D CDC42 CHRNG BBS1 CACNA1E CDH1 CHST14 BBS10 CACNA1F CDH2 CHST3 BBS12 CACNA1G CDK10 CHUK BBS2 CACNA2D2 CDK13 CILK1 BBS4 CACNB2 CDK5RAP2
    [Show full text]
  • Darkening and Eruptive Nevi During Treatment with Erlotinib
    CASE LETTER Darkening and Eruptive Nevi During Treatment With Erlotinib Stephen Hemperly, DO; Tanya Ermolovich, DO; Nektarios I. Lountzis, MD; Hina A. Sheikh, MD; Stephen M. Purcell, DO A 70-year-old man with NSCLCA presented with PRACTICE POINTS eruptive nevi and darkening of existing nevi 3 months after • Cutaneous side effects of erlotinib include acneform starting monotherapy with erlotinib. Physical examina- eruption, xerosis, paronychia, and pruritus. tion demonstrated the simultaneous appearance of scat- • Clinicians should monitor patients for darkening tered acneform papules and pustules; diffuse xerosis; and and/or eruptive nevi as well as melanoma during numerous dark copybrown to black nevi on the trunk, arms, treatment with erlotinib. and legs. Compared to prior clinical photographs taken in our office, darkening of existing medium brown nevi was noted, and new nevi developed in areas where no prior nevi had been visible (Figure 1). To the Editor: notThe patient’s medical history included 3 invasive mel- Erlotinib is a small-molecule selective tyrosine kinase anomas, all of which were diagnosed at least 7 years prior inhibitor that functions by blocking the intracellular por- to the initiation of erlotinib and were treated by surgical tion of the epidermal growth factor receptor (EGFR)Do1,2; excision alone. Prior treatment of NSCLCA consisted of a EGFR normally is expressed in the basal layer of the left lower lobectomy followed by docetaxel, carboplatin, epidermis, sweat glands, and hair follicles, and is over- pegfilgrastim, dexamethasone, and pemetrexed. A thor- expressed in some cancers.1,3 Normal activation of ough review of all of the patient’s medications revealed EGFR leads to signal transduction through the mitogen- no associations with changes in nevi.
    [Show full text]
  • Pulmonary Toxicities of Tyrosine Kinase Inhibitors
    Pulmonary Toxicities of Tyrosine Kinase Inhibitors Maajid Mumtaz Peerzada, MD, Timothy P. Spiro, MD, FACP, and Hamed A. Daw, MD Dr. Peerzada is a Resident in the Depart- Abstract: The incidence of pulmonary toxicities with the use of ment of Internal Medicine at Fairview tyrosine kinase inhibitors (TKIs) is not very high; however, various Hospital in Cleveland, Ohio. Dr. Spiro and case reports and studies continue to show significant variability in Dr. Daw are Staff Physicians at the Cleve- the incidence of these adverse events, ranging from 0.2% to 10.9%. land Clinic Foundation Cancer Center, in Cleveland, Ohio. Gefitinib and erlotinib are orally active, small-molecule inhibitors of the epidermal growth factor receptor tyrosine kinase that are mainly used to treat non-small cell lung cancer. Imatinib is an inhibitor of BCR-ABL tyrosine kinase that is used to treat various leukemias, gastrointestinal stromal tumors, and other cancers. In this article, we Address correspondence to: review data to identify the very rare but fatal pulmonary toxicities Maajid Mumtaz Peerzada, MD Medicor Associates of Chautauqua (mostly interstitial lung disease) caused by these drugs. Internal Medicine 12 Center Street Fredonia, NY 14063 Introduction Phone: 716-679-2233 E-mail: [email protected] Tyrosine kinases are enzymes that activate the phosphorylation of tyro- sine residues by transferring the terminal phosphate of ATP. Some of the tyrosine kinase inhibitors (TKIs) currently used in the treatment of various malignancies include imatinib (Gleevec, Novartis), erlotinib (Tarceva, Genentech/OSI), and gefitinib (Iressa, AstraZeneca). This article presents a basic introduction (mechanism of action and indi- cations of use) of these TKIs and summarizes the incidence, various clinical presentations, diagnosis, treatment options, and outcomes of patients around the world that presented with pulmonary toxicities caused by these drugs.
    [Show full text]
  • Bridging from Preclinical to Clinical Studies for Tyrosine Kinase Inhibitors Based on Pharmacokinetics/Pharmacodynamics and Toxicokinetics/Toxicodynamics
    Drug Metab. Pharmacokinet. 26 (6): 612­620 (2011). Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX) Regular Article Bridging from Preclinical to Clinical Studies for Tyrosine Kinase Inhibitors Based on Pharmacokinetics/Pharmacodynamics and Toxicokinetics/Toxicodynamics Azusa HOSHINO-YOSHINO1,2,MotohiroKATO2,KohnosukeNAKANO2, Masaki ISHIGAI2,ToshiyukiKUDO1 and Kiyomi ITO1,* 1Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan 2Pre-clinical Research Department, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: The purpose of this study was to provide a pharmacokinetics/pharmacodynamics and toxi- cokinetics/toxicodynamics bridging of kinase inhibitors by identifying the relationship between their clinical and preclinical (rat, dog, and monkey) data on exposure and efficacy/toxicity. For the eight kinase inhibitors approved in Japan (imatinib, gefitinib, erlotinib, sorafenib, sunitinib, nilotinib, dasatinib, and lapatinib), the human unbound area under the concentration-time curve at steady state (AUCss,u) at the clinical dose correlated well with animal AUCss,u at the no-observed-adverse-effect level (NOAEL) or maximum tolerated dose (MTD). The best correlation was observed for rat AUCss,u at the MTD (p < 0.001). Emax model analysis was performed using the efficacy of each drug in xenograft mice, and the efficacy at the human AUC of the clinical dose was evaluated. The predicted efficacy at the human AUC of the clinical dose varied from far below Emax to around Emax even in the tumor for which use of the drugs had been accepted. These results suggest that rat AUCss,u attheMTD,butnottheefficacy in xenograft mice, may be a useful parameter to estimate the human clinical dose of kinase inhibitors, which seems to be currently determined by toxicity rather than efficacy.
    [Show full text]
  • Activity of Lapatinib Is Independent of EGFR Expression Level in HER2-Overexpressing Breast Cancer Cells
    1846 Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells Dongwei Zhang,1,2 Ashutosh Pal,3 overexpressed (i.e., HER2-positive) in 20% to 30% of breast William G. Bornmann,3 Fumiyuki Yamasaki,1,2 cancers (4, 5). EGFR and HER2 are known to drive tumor Francisco J. Esteva,1,4 Gabriel N. Hortobagyi,4 growth and progression and have emerged as promising Chandra Bartholomeusz,1,2 and Naoto T. Ueno1,2,4 targets for cancer therapy. A number of small molecules that target individual or 1Breast Cancer Translational Research Laboratory, dual ErbB receptors have been developed and tested in Departments of 2Stem Cell Transplantation and Cellular 3 4 clinical trials. Lapatinib, a dual inhibitor of EGFR and Therapy, Experimental Diagnostic Imaging, and Breast HER2 tyrosine kinases, has already been approved by the Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas US Food and Drug Administration as a treatment for HER2-positive metastatic breast cancer (6, 7). Lapatinib as a single agent or in combination with trastuzumab or Abstract capecitabine exhibited activity against HER2-positive ad- Epidermal growth factor receptor (EGFR/ErbB1) and HER2 vanced or metastatic breast cancer that has progressed after (ErbB2/neu), members of the ErbB receptor tyrosine kinase trastuzumab therapy (8–10). The activity of lapatinib in family, are frequently overexpressed in breast cancer and inflammatory breast cancer was evaluated in an interna- are known to drive tumor growth and progression, making tional Phase II trial (11). Although lapatinib showed them promisingtargetsfor cancer therapy.
    [Show full text]