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Supplementary Table 5.List of the 220 Most Frequently Amplified Genes In

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Supplementary Table 5. List of the 220 most frequently amplified genes in this study. The table includes their chromosomal location, the amplification frequency in ER-positive female breast cancer with associated p-value for difference in proportions, the preference for surrogate intrinsic molecular subtype, and associations with clinical, pathological and genetic characteristics. Potentially druggable gene categories, clinical actionability and known drug interactions are indicated per gene. Gene Full name chr location % amp in FFPE % amps in FF total % amp % amp ER+ FBC* p-value MBC vs ER+ FBC** % in lumA-like % in lumB-like p-value BRCA2 germline Age Hist type ER status PR status HER2 status Grade MAI Size LN SNV load PIK3CA mut KM (OS)*** KM (5Y OS)*** druggable gene category# clinically actionable?## known drug interactions?### THBS1 thrombospondin 1 15q14 37% 9% 30% 0.1% <0.0001 23% 35% 0.128 ns ns ns ns ns ns ns ns ns ns ns ns 0.642 p=0.832 cell surface, tumor suppressor, drug resistance, external side of plasma membrane no none PRKDC protein kinase, DNA-activated, catalytic polypeptide 8q11.21 35% 7% 27% 10.9% <0.0001 26% 30% 0.595 ns ns ns ns ns ns ns ns ns ns ns ns 0.838 p=0.903 (serine threonine) kinase, druggable genome, PI3 kinase, tumor suppressor, TF complex, TF binding, DNA repair yes DNA-PK INHIBITOR V (DNA-PK inhibitor); WORTMANNIN (PI3K inhibitor); SF1126 (PI3 kinase/mTOR inhibitor) TBX3 T-box 3 12q24.21 34% 7% 27% 0.1% <0.0001 20% 35% 0.053 ns ns ns ns ns ns ns ns ns ns ns ns 0.439 p=0.264 tumor suppressor, TF binding yes none ASAP1 ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 8q24.21-q24.22 32% 7% 25% 20.2% 0.1691 20% 32% 0.123 p=0.001 ns ns ns ns ns ns ns ns ns ns ns 0.834 p=0.748 no no none RAD21 RAD21 cohesin complex component 8q24.11 32% 4% 24% 21.8% 0.4851 18% 33% 0.051 ns ns ns ns ns ns ns ns ns ns ns ns 0.908 p=0.842 DNA repair no none UBR5 Ubiquitin Protein Ligase E3 Component N-Recognin 5 8q22.3 29% 11% 24% 18.8% 0.1142 20% 32% 0.123 p=0.002 ns ns ns ns ns 0.037 (high) 0.047 (high) ns ns ns ns p=0.228 p=0.855 DNA repair no none ARNT aryl hydrocarbon receptor nuclear translocator 1q21.3 29% 9% 24% 18.6% 0.1483 24% 23% 0.905 ns ns ns ns ns p=0.003 (pos) ns ns ns ns ns p=0.011 (mut) 0.089 (poor; 17) p=0.113 TF complex, TF binding no none LAMC1 laminin subunit gamma 1 1q25.3 30% 9% 24% 23.9% 0.9584 23% 25% 0.765 ns ns ns ns ns p=0.003 (pos) ns p=0.002 (high) ns ns ns ns 0.623 p=0.667 no no none SMYD2 SET and MYND domain containing 2 1q32.3 32% 2% 24% 26.6% 0.4640 20% 32% 0.123 ns ns ns ns ns ns ns p=0.007 (high) ns ns ns ns 0.023 (poor; 19) p=0.068 (poor; 14) histone modification, methyl transferase no none SMYD3 SET and MYND domain containing 3 1q44 30% 4% 23% 24.0% 0.7943 23% 25% 0.765 ns ns ns ns ns ns p=0.023 (high) p=0.0004 (high) ns ns ns p=0.024 (mut) 0.019 (poor; 20) p=0.045 (poor; 15) histone modification, methyl transferase no none ANK1 Ankyrin 1 8p11.21 22% 20% 22% 11.5% 0.0003 20% 17% 0.660 ns ns ns ns ns ns ns ns ns ns ns ns p=0.661 p=0.826 no no none CREBBP CREB Binding Protein 16p13.3 25% 13% 22% 8.9% <0.0001 23% 20% 0.709 ns ns ns ns ns ns ns ns ns ns ns p=0.019 (no mut) p=0.590 p=0.234 tumor suppressor; TF complex; histone modification; TF binding yes ISCHEMIN; DB08655 (CREBBP inhibitors) KDM5B lysine demethylase 5B 1q32.1 30% 2% 22% 27.0% 0.2269 24% 23% 0.905 ns ns ns ns ns ns ns p=0.0004 (high) ns ns ns ns 0.149 p=0.107 histone modification no PBIT (histone demethylase inhibitor) SCYL3 SCY1 like pseudokinase 3 1q24.2 31% 0% 22% 22.4% 0.9574 20% 28% 0.256 ns ns ns ns ns ns ns p=0.009 (high) ns ns ns ns 0.007 (poor; 18) p=0.022 (poor; 14) (serine threonine) kinase, druggable genome no none TSC2 Tuberous Sclerosis 2 16p13.3 23% 20% 22% 9.4% <0.0001 23% 18% 0.543 ns ns ns ns ns ns ns ns ns ns ns ns p=0.544 p=0.067 (better; 4) tumor suppressor yes none ASH2L ASH2 Like Histone Lysine Methyltransferase Complex Subunit 8p11.23 24% 13% 21% 15.0% 0.0459 14% 30% 0.025 ns ns ns ns 0.042 (neg) ns ns ns ns ns ns ns p=0.701 p=0.619 B30_2 SPRY domain; druggable genome; histone modification no none CAPN2 calpain 2 1q41 29% 2% 21% 25.3% 0.3288 27% 17% 0.153 ns ns ns ns ns ns ns ns ns ns ns p=0.013 (mut) 0.329 p=0.681 protease, druggable genome no none CCND1 Cyclin D1 11q13.3 25% 11% 21% 19.4% 0.5560 17% 27% 0.172 ns ns ns ns ns ns ns 0.018 (high) ns ns ns ns p=0.265 p=0.128 kinase; tumor suppressor; drug resistance; TF binding yes TAMOXIFEN (SERM); ABEMACICLIB; RIBOCICLIB (CDK4/6 inhibitors) COL14A1 collagen type XIV alpha 1 chain 8q24.12 27% 7% 21% 21.0% 0.8915 18% 27% 0.253 ns ns ns ns ns ns p=0.044 (high) ns ns ns ns ns 0.545 p=0.775 druggable genome no none ELF3 E74 Like ETS Transcription Factor 3 1q32.1 26% 11% 21% 26.8% 0.1808 21% 20% 0.867 ns ns ns ns ns 0.027 (pos) ns ns ns ns ns p=0.013 (mut) p=0.068 (poor; 14) p=0.312 no no none ERBB2 Erb-B2 Receptor Tyrosine Kinase 2 17q12 24% 13% 21% 10.7% 0.0002 21% 22% 0.950 ns ns ns ns ns 0.002 (pos) ns ns p=0.008 (large) ns ns p=0.008 (mut) p=0.090 (poor; 14) p=0.126 (tyrosine) kinase; druggable genome yes AFATINIB; NERATINIB; LAPATINIB; DACOMITINIB; SAPITINIB; BMS-599626; MUBRITINIB (tyrosine kinase inhibitors) etc. OBSCN Obscurin, Cytoskeletal Calmodulin And Titin-Interacting RhoGEF 1q42.13 21% 20% 21% 24.9% 0.3799 26% 12% 0.044 ns ns ns ns ns ns ns ns p=0.008 (large) ns ns ns p=0.135 p=0.451 (serine threonine) kinase; druggable genome no none WHSC1L1 Nuclear Receptor Binding SET Domain Protein 3 8p11.23 24% 16% 21% 14.8% 0.0387 17% 25% 0.248 ns ns ns ns ns ns ns ns ns ns ns ns p=0.830 p=0.661 histone modification; methyl transferase no none COL1A1 Collagen Type I Alpha 1 Chain 17q21.33 23% 13% 21% 6.7% <0.0001 18% 17% 0.823 ns ns ns ns ns ns ns ns p=0.012 (large) ns p=0.035 (high) ns p=0.035 (poor; 15) p=0.091 (poor; 11) drug resistance no HALOFUGINONE (COL1A1/MMP2 inhibitor); ZOLEDRONIC ACID (bisphosphonate) FGFR1 Fibroblast Growth Factor Receptor 1 8p11.23 23% 13% 21% 14.6% 0.0324 15% 23% 0.243 ns ns ns ns ns ns ns ns ns ns ns ns p=0.702 p=0.296 druggable genome; (tyrosine) kinase; tumor suppressor yes PONATINIB; NINTEDANIB; DOVITINIB; SORAFENIB; LENVATINIB; ENMD-2076 (tyrosine kinase inhibitors) etc. IKBKB Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Beta 8p11.21 22% 16% 21% 10.7% 0.0002 20% 20% 0.966 ns ns ns ns ns ns ns ns ns ns p=0.011 (high) ns p=0.035 (better; 6) p=0.039 (better; 3) druggable genome; (serine threonine) kinase; drug resistance no AURANOFIN; SULFASALAZINE (antirheumatic agents) LAMB3 Laminin Subunit Beta 3 1q32.2 21% 18% 21% 27.6% 0.1268 23% 15% 0.270 ns ns ns ns ns 0.021 (pos) ns ns ns ns ns ns p=0.808 p=0.471 no no none LRP2 LDL Receptor Related Protein 2 2q31.1 23% 13% 21% 0.0% <0.0001 20% 18% 0.846 ns ns ns ns ns ns ns ns ns ns ns ns p=0.673 p=0.812 no no none PARP1 poly(ADP-ribose) polymerase 1 1q42.12 26% 7% 21% 25.1% 0.3537 23% 18% 0.543 ns ns ns ns ns ns ns ns ns ns ns ns 0.111 p=0.200 druggable genome, TF complex, TF binding, DNA repair yes VELIPARIB; RUCAPARIB; OLAPARIB; 3-METHOXYBENZAMIDE; NU1025; NICOTINAMIDE (PARP inhibitors); INIPARIB (unknown) etc TEX14 testis expressed 14, intercellular bridge forming factor 17q22 25% 9% 21% 9.1% <0.0001 14% 25% 0.105 ns ns ns ns p=0.004 (neg) p=0.001 (pos) p=0.040 (high) ns ns ns ns ns 0.71 p=0.895 (tyrosine) kinase, tumor suppressor, druggable genome no none CIT Citron Rho-Interacting Serine/Threonine Kinase 12q24.23 20% 18% 20% 0.2% <0.0001 18% 17% 0.823 ns ns ns ns ns ns ns ns ns ns ns ns p=0.154 p=0.802 (serine threonine) kinase; tumor suppressor; druggable genome no none CSMD3 CUB and Sushi multiple domains 3 8q23.3 25% 7% 20% 21.3% 0.7234 15% 27% 0.111 p=0.001 ns ns ns ns ns ns p=0.028 (high) ns ns ns ns 0.539 p=0.970 no no none LAMA5 Laminin Subunit Alpha 5 20q13.33 20% 18% 20% 7.0% <0.0001 20% 18% 0.846 ns ns ns ns ns ns ns ns ns ns ns ns p=0.308 p=0.232 no no none MAP3K15 Mitogen-Activated Protein Kinase Kinase Kinase 15 Xp22.12 18% 22% 20% 0.7% <0.0001 23% 12% 0.102 ns ns ns ns ns ns ns ns ns ns ns ns p=0.793 p=0.761 (serine threonine) kinase; druggable genome no none PTK2 protein tyrosine kinase 2 8q24.3 28% 0% 20% 18.5% 0.6682 20% 22% 0.785 ns ns ns ns ns ns ns ns ns ns ns ns 0.359 p=0.303 (tyrosine) kinase, druggable genome no MASITINIB; ENMD-2076 (tyrosine kinase inhibitors) FZD6 frizzled class receptor 6 8q22.3 26% 2% 19% 18.7% 0.8642 17% 23% 0.349 p=0.010 ns ns ns ns ns ns ns ns ns ns ns 0.735 p=0.499 G protein coupled receptor, druggable genome, cell surface no none HDAC5 Histone Deacetylase 5 17q21.31 20% 16% 19% 0.8% <0.0001 23% 12% 0.102 ns ns ns ns ns ns ns ns p=0.009 (large) ns ns ns p=0.154 p=0.959 drug resistance; histone modification; TF binding no BELINOSTAT; DACINOSTAT; GIVINOSTAT; PANOBINOSTAT; ROMIDEPSIN; VORINOSTAT (HDAC inhibitors) etc.
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    CUSTOM KINASE SUBSTRATE PROFILING (CKSP) SERVICE List of Available Active Protein Kinases This list may change with respect to availability and pricing. Protein Kinase Name Code U.S. Protein Kinase Name Code U.S. Price Price Abl1 AB01 $200.00 BUBR1(BUB1B) BU01 $600.00 Abl1 [E255K] AB02 $400.00 CaMK1δ (CAMK1D) CA03 $200.00 Abl1 [G250E] AB03 $400.00 CAMK1γ CA04 $200.00 Abl1 [H369P] AB04 $600.00 CAMK2α (CAMK2B) CA05 $200.00 Abl1 [T315I] AB05 $400.00 CaMK2β (CAMK2B) CA06 $200.00 Abl1 [Y253F] AB06 $400.00 CaMK2δ (CAMK2D) CA07 $400.00 Abl1 [M351T] AB07 $600.00 CaMK2γ (CAMK2G) CA08 $600.00 Abl1 [Q252H] AB08 $600.00 CAMK3γ CA09 $200.00 Abl2 (Arg) AB09 $200.00 CAMK4 CA10 $200.00 ACK AC01 $200.00 CAMK4 (CaMKIV ) CA11 $400.00 ACVR1 (ALK2 ) AC02 $400.00 CAMKK1 (CAMKKA ) CA12 $200.00 ACVRL1 AC03 $400.00 CAMKK2 CA13 $200.00 ADRBK1 (GRK2) AD01 $200.00 CAMKK2 (CaMKK beta ) CA14 $400.00 ADRBK2 (GRK3) AD02 $400.00 CDC42 BPA (MRCKA ) CD01 $400.00 Akt1/PKBα AK01 $200.00 CDC42 BPB (MRCKB ) CD02 $400.00 Akt1/PKBα [δPH, S473D] AK02 $600.00 CDC7/ASK CD03 $600.00 Akt1/PKBα [δPH] AK03 $600.00 CDK1/cyclin B1 CD04 $400.00 Akt2/PKBβ AK04 $200.00 CDK1/CyclinA2 CD05 $200.00 Akt2/PKBβ [δPH, S474D] AK05 $600.00 CDK2/cyclin A CD06 $400.00 Akt3/PKBγ AK06 $200.00 CDK2/Cyclin E1 CD07 $600.00 Akt3/PKBγ [S472D] AK07 $600.00 CDK2/CyclinA2 CD08 $200.00 ALK1 AL01 $200.00 CDK3/Cyclin E1 CD09 $600.00 ALK4 (ACVR1B) AL02 $200.00 CDK4//Cyclin D3 CD10 $600.00 AMPKα1/β1/γ1 (PRKAA1/B1/G1) AM01 $200.00 CDK4/Cyclin D1 CD11 $200.00 AMPKα1/β1/γ2 (PRKAA1/B1/G2) AM02 $200.00 CDK5 CD12 $600.00
  • Src-Family Kinases Impact Prognosis and Targeted Therapy in Flt3-ITD+ Acute Myeloid Leukemia

    Src-Family Kinases Impact Prognosis and Targeted Therapy in Flt3-ITD+ Acute Myeloid Leukemia

    Src-Family Kinases Impact Prognosis and Targeted Therapy in Flt3-ITD+ Acute Myeloid Leukemia Title Page by Ravi K. Patel Bachelor of Science, University of Minnesota, 2013 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2019 Commi ttee Membership Pa UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE Commi ttee Membership Page This dissertation was presented by Ravi K. Patel It was defended on May 31, 2019 and approved by Qiming (Jane) Wang, Associate Professor Pharmacology and Chemical Biology Vaughn S. Cooper, Professor of Microbiology and Molecular Genetics Adrian Lee, Professor of Pharmacology and Chemical Biology Laura Stabile, Research Associate Professor of Pharmacology and Chemical Biology Thomas E. Smithgall, Dissertation Director, Professor and Chair of Microbiology and Molecular Genetics ii Copyright © by Ravi K. Patel 2019 iii Abstract Src-Family Kinases Play an Important Role in Flt3-ITD Acute Myeloid Leukemia Prognosis and Drug Efficacy Ravi K. Patel, PhD University of Pittsburgh, 2019 Abstract Acute myelogenous leukemia (AML) is a disease characterized by undifferentiated bone-marrow progenitor cells dominating the bone marrow. Currently the five-year survival rate for AML patients is 27.4 percent. Meanwhile the standard of care for most AML patients has not changed for nearly 50 years. We now know that AML is a genetically heterogeneous disease and therefore it is unlikely that all AML patients will respond to therapy the same way. Upregulation of protein-tyrosine kinase signaling pathways is one common feature of some AML tumors, offering opportunities for targeted therapy.
  • Autophagy Processes Are Dependent on EGF Receptor Signaling

    Autophagy Processes Are Dependent on EGF Receptor Signaling

    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 54), pp: 30289-30303 Research Paper Autophagy processes are dependent on EGF receptor signaling Vincenzo De Iuliis1, Antonio Marino1, Marika Caruso1, Sabrina Capodifoglio1, Vincenzo Flati2, Anna Marynuk3, Valeria Marricareda3, Sebastiano Ursi1, Paola Lanuti4, Claudio Talora5, Pio Conti6, Stefano Martinotti1,7 and Elena Toniato7 1Unit of Predictive Medicine, SS Annunziata University Hospital of Chieti, Chieti, Italy 2Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3Odessa National Medical University, Odesa, Odessa Oblsat, Ucraina 4Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti, Chieti, Italy 5Department of Molecular Medicine, University of Rome “La Sapienza”, Rome, Italy 6Postgraduate Medical School, University of Chieti, Chieti, Italy 7Department of Medical, Oral and Biotechnological Sciences, University G. d’Annunzio of Chieti, Chieti, Italy Correspondence to: Elena Toniato, email: [email protected] Keywords: apoptosis; autophagy; Beclin 1; EGF receptor; MAPK pathway Received: May 03, 2018 Accepted: June 13, 2018 Published: July 13, 2018 Copyright: De Iuliis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Autophagy is a not well-understood conserved mechanism activated during nutritional deprivation in order to maintain cellular homeostasis. In the present study, we investigated the correlations between autophagy, apoptosis and the MAPK pathways in melanoma cell lines. We demonstrated that during starvation the EGF receptor mediated signaling activates many proteins involved in the MAPK pathway.