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Outlier Kinase Expression by RNA Sequencing As Targets for Precision Therapy
Published OnlineFirst February 5, 2013; DOI: 10.1158/2159-8290.CD-12-0336 RESEARCH ARTICLE Outlier Kinase Expression by RNA Sequencing as Targets for Precision Therapy Vishal Kothari 1 , Iris Wei 2 , Sunita Shankar 1 , 3 , Shanker Kalyana-Sundaram 1 , 3 , 8 , Lidong Wang 2 , Linda W. Ma 1 , Pankaj Vats 1 , Catherine S. Grasso 1 , Dan R. Robinson 1 , 3 , Yi-Mi Wu 1 , 3 , Xuhong Cao 7 , Diane M. Simeone 2 , 4 , 5 , Arul M. Chinnaiyan 1 , 3 , 4 , 6 , 7 , and Chandan Kumar-Sinha 1 , 3 ABSTRACT Protein kinases represent the most effective class of therapeutic targets in cancer; therefore, determination of kinase aberrations is a major focus of cancer genomic studies. Here, we analyzed transcriptome sequencing data from a compendium of 482 cancer and benign samples from 25 different tissue types, and defi ned distinct “outlier kinases” in individual breast and pancreatic cancer samples, based on highest levels of absolute and differential expression. Frequent outlier kinases in breast cancer included therapeutic targets like ERBB2 and FGFR4 , distinct from MET , AKT2 , and PLK2 in pancreatic cancer. Outlier kinases imparted sample-specifi c depend- encies in various cell lines, as tested by siRNA knockdown and/or pharmacologic inhibition. Outlier expression of polo-like kinases was observed in a subset of KRAS -dependent pancreatic cancer cell lines, and conferred increased sensitivity to the pan-PLK inhibitor BI-6727. Our results suggest that outlier kinases represent effective precision therapeutic targets that are readily identifi able through RNA sequencing of tumors. SIGNIFICANCE: Various breast and pancreatic cancer cell lines display sensitivity to knockdown or pharmacologic inhibition of sample-specifi c outlier kinases identifi ed by high-throughput transcrip- tome sequencing. -
Supplementary Information Material and Methods
MCT-11-0474 BKM120: a potent and specific pan-PI3K inhibitor Supplementary Information Material and methods Chemicals The EGFR inhibitor NVP-AEE788 (Novartis), the Jak inhibitor I (Merck Calbiochem, #420099) and anisomycin (Alomone labs, # A-520) were prepared as 50 mM stock solutions in 100% DMSO. Doxorubicin (Adriablastin, Pfizer), EGF (Sigma Ref: E9644), PDGF (Sigma, Ref: P4306) and IL-4 (Sigma, Ref: I-4269) stock solutions were prepared as recommended by the manufacturer. For in vivo administration: Temodal (20 mg Temozolomide capsules, Essex Chemie AG, Luzern) was dissolved in 4 mL KZI/glucose (20/80, vol/vol); Taxotere was bought as 40 mg/mL solution (Sanofi Aventis, France), and prepared in KZI/glucose. Antibodies The primary antibodies used were as follows: anti-S473P-Akt (#9271), anti-T308P-Akt (#9276,), anti-S9P-GSK3β (#9336), anti-T389P-p70S6K (#9205), anti-YP/TP-Erk1/2 (#9101), anti-YP/TP-p38 (#9215), anti-YP/TP-JNK1/2 (#9101), anti-Y751P-PDGFR (#3161), anti- p21Cip1/Waf1 (#2946), anti-p27Kip1 (#2552) and anti-Ser15-p53 (#9284) antibodies were from Cell Signaling Technologies; anti-Akt (#05-591), anti-T32P-FKHRL1 (#06-952) and anti- PDGFR (#06-495) antibodies were from Upstate; anti-IGF-1R (#SC-713) and anti-EGFR (#SC-03) antibodies were from Santa Cruz; anti-GSK3α/β (#44610), anti-Y641P-Stat6 (#611566), anti-S1981P-ATM (#200-301), anti-T2609 DNA-PKcs (#GTX24194) and anti- 1 MCT-11-0474 BKM120: a potent and specific pan-PI3K inhibitor Y1316P-IGF-1R were from Bio-Source International, Becton-Dickinson, Rockland, GenTex and internal production, respectively. The 4G10 antibody was from Millipore (#05-321MG). -
Profiling Data
Compound Name DiscoveRx Gene Symbol Entrez Gene Percent Compound Symbol Control Concentration (nM) JNK-IN-8 AAK1 AAK1 69 1000 JNK-IN-8 ABL1(E255K)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317I)-nonphosphorylated ABL1 87 1000 JNK-IN-8 ABL1(F317I)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317L)-nonphosphorylated ABL1 65 1000 JNK-IN-8 ABL1(F317L)-phosphorylated ABL1 61 1000 JNK-IN-8 ABL1(H396P)-nonphosphorylated ABL1 42 1000 JNK-IN-8 ABL1(H396P)-phosphorylated ABL1 60 1000 JNK-IN-8 ABL1(M351T)-phosphorylated ABL1 81 1000 JNK-IN-8 ABL1(Q252H)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(Q252H)-phosphorylated ABL1 56 1000 JNK-IN-8 ABL1(T315I)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(T315I)-phosphorylated ABL1 92 1000 JNK-IN-8 ABL1(Y253F)-phosphorylated ABL1 71 1000 JNK-IN-8 ABL1-nonphosphorylated ABL1 97 1000 JNK-IN-8 ABL1-phosphorylated ABL1 100 1000 JNK-IN-8 ABL2 ABL2 97 1000 JNK-IN-8 ACVR1 ACVR1 100 1000 JNK-IN-8 ACVR1B ACVR1B 88 1000 JNK-IN-8 ACVR2A ACVR2A 100 1000 JNK-IN-8 ACVR2B ACVR2B 100 1000 JNK-IN-8 ACVRL1 ACVRL1 96 1000 JNK-IN-8 ADCK3 CABC1 100 1000 JNK-IN-8 ADCK4 ADCK4 93 1000 JNK-IN-8 AKT1 AKT1 100 1000 JNK-IN-8 AKT2 AKT2 100 1000 JNK-IN-8 AKT3 AKT3 100 1000 JNK-IN-8 ALK ALK 85 1000 JNK-IN-8 AMPK-alpha1 PRKAA1 100 1000 JNK-IN-8 AMPK-alpha2 PRKAA2 84 1000 JNK-IN-8 ANKK1 ANKK1 75 1000 JNK-IN-8 ARK5 NUAK1 100 1000 JNK-IN-8 ASK1 MAP3K5 100 1000 JNK-IN-8 ASK2 MAP3K6 93 1000 JNK-IN-8 AURKA AURKA 100 1000 JNK-IN-8 AURKA AURKA 84 1000 JNK-IN-8 AURKB AURKB 83 1000 JNK-IN-8 AURKB AURKB 96 1000 JNK-IN-8 AURKC AURKC 95 1000 JNK-IN-8 -
Application of a MYC Degradation
SCIENCE SIGNALING | RESEARCH ARTICLE CANCER Copyright © 2019 The Authors, some rights reserved; Application of a MYC degradation screen identifies exclusive licensee American Association sensitivity to CDK9 inhibitors in KRAS-mutant for the Advancement of Science. No claim pancreatic cancer to original U.S. Devon R. Blake1, Angelina V. Vaseva2, Richard G. Hodge2, McKenzie P. Kline3, Thomas S. K. Gilbert1,4, Government Works Vikas Tyagi5, Daowei Huang5, Gabrielle C. Whiten5, Jacob E. Larson5, Xiaodong Wang2,5, Kenneth H. Pearce5, Laura E. Herring1,4, Lee M. Graves1,2,4, Stephen V. Frye2,5, Michael J. Emanuele1,2, Adrienne D. Cox1,2,6, Channing J. Der1,2* Stabilization of the MYC oncoprotein by KRAS signaling critically promotes the growth of pancreatic ductal adeno- carcinoma (PDAC). Thus, understanding how MYC protein stability is regulated may lead to effective therapies. Here, we used a previously developed, flow cytometry–based assay that screened a library of >800 protein kinase inhibitors and identified compounds that promoted either the stability or degradation of MYC in a KRAS-mutant PDAC cell line. We validated compounds that stabilized or destabilized MYC and then focused on one compound, Downloaded from UNC10112785, that induced the substantial loss of MYC protein in both two-dimensional (2D) and 3D cell cultures. We determined that this compound is a potent CDK9 inhibitor with a previously uncharacterized scaffold, caused MYC loss through both transcriptional and posttranslational mechanisms, and suppresses PDAC anchorage- dependent and anchorage-independent growth. We discovered that CDK9 enhanced MYC protein stability 62 through a previously unknown, KRAS-independent mechanism involving direct phosphorylation of MYC at Ser . -
Lipid Metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives
cancers Review Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives 1, 1, 1 2 1 Laurence Pellerin y, Lorry Carrié y , Carine Dufau , Laurence Nieto , Bruno Ségui , 1,3 1, , 1, , Thierry Levade , Joëlle Riond * z and Nathalie Andrieu-Abadie * z 1 Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Fondation ARC, Université Fédérale de Toulouse Midi-Pyrénées, Université Toulouse III Paul-Sabatier, Inserm 1037, 2 avenue Hubert Curien, tgrCS 53717, 31037 Toulouse CEDEX 1, France; [email protected] (L.P.); [email protected] (L.C.); [email protected] (C.D.); [email protected] (B.S.); [email protected] (T.L.) 2 Institut de Pharmacologie et de Biologie Structurale, CNRS, Université Toulouse III Paul-Sabatier, UMR 5089, 205 Route de Narbonne, 31400 Toulouse, France; [email protected] 3 Laboratoire de Biochimie Métabolique, CHU Toulouse, 31059 Toulouse, France * Correspondence: [email protected] (J.R.); [email protected] (N.A.-A.); Tel.: +33-582-7416-20 (J.R.) These authors contributed equally to this work. y These authors jointly supervised this work. z Received: 15 September 2020; Accepted: 23 October 2020; Published: 27 October 2020 Simple Summary: Melanoma is a devastating skin cancer characterized by an impressive metabolic plasticity. Melanoma cells are able to adapt to the tumor microenvironment by using a variety of fuels that contribute to tumor growth and progression. In this review, the authors summarize the contribution of the lipid metabolic network in melanoma plasticity and aggressiveness, with a particular attention to specific lipid classes such as glycerophospholipids, sphingolipids, sterols and eicosanoids. -
Novel Functions of Death-Associated Protein Kinases Through Mitogen-Activated Protein Kinase-Related Signals
International Journal of Molecular Sciences Article Novel Functions of Death-Associated Protein Kinases through Mitogen-Activated Protein Kinase-Related Signals Mohamed Elbadawy 1,2,† , Tatsuya Usui 1,*,†, Hideyuki Yamawaki 3 and Kazuaki Sasaki 1 1 Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; [email protected] (M.E.); [email protected] (K.S.) 2 Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Elqaliobiya, Toukh 13736, Egypt 3 Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan; [email protected] * Correspondence: [email protected]; Tel./Fax: +81-42-367-5769 † These authors contributed equally to this work. Received: 13 September 2018; Accepted: 1 October 2018; Published: 4 October 2018 Abstract: Death associated protein kinase (DAPK) is a calcium/calmodulin-regulated serine/threonine kinase; its main function is to regulate cell death. DAPK family proteins consist of DAPK1, DAPK2, DAPK3, DAPK-related apoptosis-inducing protein kinases (DRAK)-1 and DRAK-2. In this review, we discuss the roles and regulatory mechanisms of DAPK family members and their relevance to diseases. Furthermore, a special focus is given to several reports describing cross-talks between DAPKs and mitogen-activated protein kinases (MAPK) family members in various pathologies. We also discuss small molecule inhibitors of DAPKs and their potential as therapeutic targets against human diseases. Keywords: MAPK; DAPK; ERK; p38; JNK 1. Introduction: DAPKs, MAPKs Death-associated protein kinase (DAPK) family proteins are closely related, Ca2+/calmodulin (CaM)-regulated serine/threonine kinases, whose members not only possess significant homology in their catalytic domains but also share cell death-associated functions [1,2]. -
GAK (1C2): Sc-56903
SANTA CRUZ BIOTECHNOLOGY, INC. GAK (1C2): sc-56903 The Power to Question BACKGROUND SOURCE Cyclins are the regulatory subunits of Cdc2 p34 and related cyclin-dependent GAK (1C2) is a mouse monoclonal antibody raised against amino acids kinases (Cdks) which play critical roles in the control of cell cycle progression. 1-1305 of GAK of rat origin. The catalytic subunit for cyclin A and B is Cdc2 p34 kinase. The Cdc2-cyclin This product has been manufactured by MBL International Corporation. B complex controls the G2 to M transition, whereas Cdc2-cyclin A regulates S phase progression. The G to S transition, however, appears to be controlled 1 PRODUCT by the G1 cyclins. Cyclin D1 accumulates during G1 and associates with Cdk2, Each vial contains 100 µg IgG in 1.0 ml of PBS with < 0.1% sodium azide, Cdk4 and Cdk5. Cyclin E and Cdk2 interact during the G1 to S transition. 1 Cyclin G contains a typical N-terminal cyclin box and a C-terminal domain 0.1% gelatin and 5% glycerol. sequence homologous to the tyrosine phosphorylation site of the epidermal growth factor receptor. Cyclin G expression is induced within three hours after APPLICATIONS growth stimulation and remains elevated with no apparent cell cycle depen- GAK (1C2) is recommended for detection of GAK of mouse, rat and human dency. A serine/threonine kinase, designated GAK for cyclin G associated origin by Western Blotting (starting dilution 1:200, dilution range 1:100- kinase, has been identified. GAK has been shown to bind directly to cyclin G 1:1000). -
1 Kinobead Profiling Reveals Reprogramming of B-Cell Receptor Signaling in Response to Therapy Within Primary CLL Cells. Linley
bioRxiv preprint doi: https://doi.org/10.1101/841312; this version posted November 14, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Kinobead profiling reveals reprogramming of B-cell receptor signaling in response to therapy within primary CLL cells. Linley AJ1, Griffin R2, Cicconi S2, D’Avola A3$, MacEwan DJ4, Pettit AR1, Kalakonda N1, Packham G3, Prior IA5, Slupsky JR1. 1. Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK. 2. CRUK Clinical Trials Unit, University of Liverpool, Waterhouse Building, Ashton Street, Liverpool. 3. Southampton Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. 4. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK. 5. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Nuffield Wing, Crown Street, Liverpool, UK. $ Current Address: The Francis Crick Institute, 1 Midland Road, London, UK. Corresponding author: Dr Adam J Linley, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK; [email protected]; +44(0)151 794 5310 Running head: Therapy brings about BCR signal changes. Key points 1. sIgM signaling patterns alter following in vivo therapy using either chemoimmunotherapy or ibrutinib. 2. Kinobeads provide a novel method for high-resolution investigation of signaling in primary CLL cells. 1 bioRxiv preprint doi: https://doi.org/10.1101/841312; this version posted November 14, 2019. -
Novel Methylation Patterns Predict Outcome in Uveal Melanoma
Article Novel Methylation Patterns Predict Outcome in Uveal Melanoma Sarah Tadhg Ferrier 1 and Julia Valdemarin Burnier 1,2,3,* 1 Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada, H4A 3J1; [email protected] 2 Experimental Pathology Unit, Department of Pathology, McGill University; Montreal, QC, Canada, H3A 0G4 3 Department of Oncology, McGill University; Montreal, QC, Canada, H3A 0G4 * Correspondence: [email protected] Table S1. Differentially methylated genes in the Pathways in Cancer KEGG pathway with a log FC ≥ 1.5. Average Average Log Fold Change Differentially Adjusted P Beta Beta ID Gene Name Species (High vs Low Methylated Probes Value Value, Value, Risk) Low High ABL proto-oncogene 1, non- ABL1 Homo sapiens cg13440206, −1.85238 1.39E−06 0.576589 0.259088 receptor tyrosine kinase(ABL1) cg02915920 −1.84042 8.03E−06 0.482846 0.192714 cg21195763 1.685721 3.13E−19 0.573548 0.83358 ADCY2 adenylate cyclase 2(ADCY2) Homo sapiens cg14116052 2.454448 4.3E−24 0.513149 0.885217 ADCY6 adenylate cyclase 6(ADCY6) Homo sapiens cg25196508 3.480923 2.9E−25 0.188362 0.792499 AKT serine/threonine kinase AKT1 Homo sapiens cg14116052 2.454448 4.3E−24 0.513149 0.885217 1(AKT1) bone morphogenetic protein BMP4 Homo sapiens cg08046044 1.527233 3.98E−06 0.049923 0.209543 4(BMP4) cg01873886 1.789942 2.55E−05 0.026254 0.1723 Life 2020, 10, x; doi: FOR PEER REVIEW www.mdpi.com/journal/life Life 2020, 10, x FOR PEER REVIEW 2 of 22 cyclin dependent kinase inhibitor CDKN1B Homo sapiens cg06197769 -
Inhibition of ERK 1/2 Kinases Prevents Tendon Matrix Breakdown Ulrich Blache1,2,3, Stefania L
www.nature.com/scientificreports OPEN Inhibition of ERK 1/2 kinases prevents tendon matrix breakdown Ulrich Blache1,2,3, Stefania L. Wunderli1,2,3, Amro A. Hussien1,2, Tino Stauber1,2, Gabriel Flückiger1,2, Maja Bollhalder1,2, Barbara Niederöst1,2, Sandro F. Fucentese1 & Jess G. Snedeker1,2* Tendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon. Here, we show that the extracellular-signal regulated kinase (ERK) pathway is central in tendon degradation of load-deprived tissue explants. We show that ERK 1/2 are highly phosphorylated in mechanically unloaded tendon fascicles in a vascular niche-dependent manner. Pharmacological inhibition of ERK 1/2 abolishes the induction of ECM catabolic gene expression (MMPs) and fully prevents loss of mechanical properties. Moreover, ERK 1/2 inhibition in unloaded tendon fascicles suppresses features of pathological tissue remodeling such as collagen type 3 matrix switch and the induction of the pro-fbrotic cytokine interleukin 11. This work demonstrates ERK signaling as a central checkpoint to trigger tendon matrix degradation and remodeling using load-deprived tissue explants. Tendon is a musculoskeletal tissue that transmits muscle force to bone. To accomplish its biomechanical function, tendon tissues adopt a specialized extracellular matrix (ECM) structure1. Te load-bearing tendon compart- ment consists of highly aligned collagen-rich fascicles that are interspersed with tendon stromal cells. Tendon is a mechanosensitive tissue whereby physiological mechanical loading is vital for maintaining tendon archi- tecture and homeostasis2. Mechanical unloading of the tissue, for instance following tendon rupture or more localized micro trauma, leads to proteolytic breakdown of the tissue with severe deterioration of both structural and mechanical properties3–5. -
PRODUCTS and SERVICES Target List
PRODUCTS AND SERVICES Target list Kinase Products P.1-11 Kinase Products Biochemical Assays P.12 "QuickScout Screening Assist™ Kits" Kinase Protein Assay Kits P.13 "QuickScout Custom Profiling & Panel Profiling Series" Targets P.14 "QuickScout Custom Profiling Series" Preincubation Targets Cell-Based Assays P.15 NanoBRET™ TE Intracellular Kinase Cell-Based Assay Service Targets P.16 Tyrosine Kinase Ba/F3 Cell-Based Assay Service Targets P.17 Kinase HEK293 Cell-Based Assay Service ～ClariCELL™ ～ Targets P.18 Detection of Protein-Protein Interactions ～ProbeX™～ Stable Cell Lines Crystallization Services P.19 FastLane™ Structures ～Premium～ P.20-21 FastLane™ Structures ～Standard～ Kinase Products For details of products, please see "PRODUCTS AND SERVICES" on page 1～3. Tyrosine Kinases Note: Please contact us for availability or further information. Information may be changed without notice. Expression Protein Kinase Tag Carna Product Name Catalog No. Construct Sequence Accession Number Tag Location System HIS ABL(ABL1) 08-001 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) ABL(ABL1) BTN BTN-ABL(ABL1) 08-401-20N Full-length 2-1130 NP_005148.2 N-terminal DYKDDDDK Insect (sf21) ABL(ABL1) [E255K] HIS ABL(ABL1)[E255K] 08-094 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) HIS ABL(ABL1)[T315I] 08-093 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) ABL(ABL1) [T315I] BTN BTN-ABL(ABL1)[T315I] 08-493-20N Full-length 2-1130 NP_005148.2 N-terminal DYKDDDDK Insect (sf21) ACK(TNK2) GST ACK(TNK2) 08-196 Catalytic domain -
(12) United States Patent (10) Patent No.: US 8,148,089 B2 Anderson Et Al
US008148089B2 (12) United States Patent (10) Patent No.: US 8,148,089 B2 Anderson et al. (45) Date of Patent: Apr. 3, 2012 (54) ALPHA-SYNUCLEIN KINASE FOREIGN PATENT DOCUMENTS (75) Inventors: John P. Anderson, San Francisco, CA WO WO 2006/073734 A2 T 2006 WO WO 2006/1248.92 A2 11/2006 (US); Kelly Banducci, Pleasanton, CA WO WO 2004/069175 A2 8, 2007 (US); Guriobal S. Basi, Palo Alto, CA WO WO 2007/089862 A2 8, 2007 (US); David Chereau, San Mateo, CA WO WO 2009/103010 A2 8, 2009 (US); Tamie J. Chilcote, San Francisco, CA (US); Normand L. Frigon, Jr., OTHER PUBLICATIONS Millbrae, CA (US); Jason Goldstein, U.S. Appl. No. 61/053,632, filed May 15, 2008, Anderson et al. Burlingame, CA (US); Irene Griswold, Anderson et al., “Phosphorylation of Ser-129 is the Dominant Patho San Francisco, CA (US) logical Modification of Alpha-Synclein in Familial and Sporadic Lewy Body Disease.” Journal of Biological Chemistry, 281 (73) Assignee: Elan Pharma International Limited, (40):29739-29752 (2006). Dublin (IE) Chen et al., “Alpha-Synuclein Phosphorylation Controls Neurotoxic ity and Inclusion Formation in a Drosophila Model of Parkinson (*) Notice: Subject to any disclaimer, the term of this Disease.” Nature Neuroscience, 8(5):657-663 (2005). patent is extended or adjusted under 35 Ellis et al., “Alpha-Synuclein is Phosphorylated by Members of the SCR Family of Protein-Tyrosine Kinases,” Journal of Biological U.S.C. 154(b) by 167 days. Chemistry, 276 (6):3879-3884 (2001). Inglis et al., “Polo-like kinase 2 (PLK2) phosphorylates alpha (21) Appl.