Uwe Rix, PhD
Researcher

Uwe Rix, PhD

Academic Rank: Assistant Member

Overview

Most drugs are unspecific.  They are 'dirty' drugs'.  We can use this property to learn more about oncogenic signaling and target cancer where it is most vulnerable.

Discipline

    • Drug Discovery
    • Thoracic Oncology
    • Lung Cancer Center of Excellence
    • Chemical Biology and Molecular Medicine Program
    • Systems Medicine Working Group

Education & Training

    • GAU Gottingen, Germany, MS - Chemistry
    • MUSC, Charleston, PhD - Pharmaceutical Sciences
    • University of Kentucky College of Pharmacy, Postdoctoral Fellow - Pharmaceutical Sciences
    • Austrian Academy of Sciences Center for Molecular Medicine, Postdoctoral Fellow - Molecular Medicine
    • Austrian Academy of Sciences Center for Molecular Medicine, Senior Postdoctoral Fellow - Molecular Medicine
Research

My scientific interest centers on chemical biology, targeted drugs, drug-protein interaction networks, synergy and molecular mechanisms of action in the context of cancer research, particularly lung cancer research. I am pursuing a multi-layered chemical biology/systems pharmacology strategy based on the systematic screening for drug synergy and subsequent identification of the molecular basis underlying the observed synergy by for instance combining chemical proteomics, phosphoproteomics and transcriptomics approaches. This integrated strategy can identify on one hand novel synergistic drug combinations, which due to the focus on clinical drug candidates will have high potential for translation into clinical settings. In addition, the mechanistic understanding will help to further dissect complex oncogenic signaling networks, as well as providing potential mechanism-based biomarkers that can guide patient stratification for future clinical trials of the respective drug combinations. My core expertise lies in chemical proteomics, which is a postgenomic adaptation of classical drug-affinity chromatography that is powered by downstream mass spectrometry and bioinformatics analysis. This technology is optimally suited to support systematic investigations of cellular drug activities and mechanisms of action by characterizing in an unbiased fashion the cell-specific native drug-target interaction profiles, which are important starting points for identifying the engaged signaling pathways and networks. By applying this strategy, we have been able to identify a large number of new drug-protein interactions, predict drug side effects, characterize circuitries of oncogenic signaling and identify novel synergistic drug combinations.

Publications

  • Kuenzi BM, Remsing Rix LL, Stewart PA, Fang B, Kinose F, Bryant AT, Boyle TA, Koomen JM, Haura EB, Rix U. Polypharmacology-based ceritinib repurposing using integrated functional proteomics. Nat Chem Biol. 2017 Oct. Pubmedid: 28991240.
  • Verduzco D, Kuenzi BM, Kinose F, Sondak VK, Eroglu Z, Rix U, Smalley KSM. Ceritinib enhances the efficacy of trametinib in BRAF/NRAS-wild type melanoma cell lines. Mol Cancer Ther. 2017 Nov. Pubmedid: 29133622.
  • Phadke M, Rix LLR, Smalley I, Bryant AT, Luo Y, Lawrence HR, Schaible BJ, Chen YA, Rix U, Smalley KSM. Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition. Mol Oncol. 2017 Nov. Pubmedid: 29112787.
  • Wright G, Golubeva V, Remsing Rix LL, Berndt N, Luo Y, Ward GA, Gray JE, Schönbrunn E, Lawrence HR, Monteiro ANA, Rix U. Dual Targeting of WEE1 and PLK1 by AZD1775 Elicits Single Agent Cellular Anticancer Activity. Acs Chem Biol. 2017 Jul;12(7):1883-1892. Pubmedid: 28557434. Pmcid: PMC5551971.
  • Vaishnavi A, Schubert L, Rix U, Marek LA, Le AT, Keysar S, Glogowska MJ, Smith MA, Kako SL, Sumi NJ, Davies KD, Ware KE, Varella-Garcia M, Haura EB, Jimeno A, Heasley LE, Aisner DL, Doebele RC. EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases. Cancer Res. 2017 Jul;77(13):3551-3563. Pubmedid: 28428274. Pmcid: PMC5516930.
  • Gao B, Huang C, Kernstine K, Pelekanou V, Kluger Y, Jiang T, Peters-Hall JR, Coquelin M, Girard L, Zhang W, Huffman K, Oliver D, Kinose F, Haura E, Teer JK, Rix U, Le AT, Aisner DL, Varella-Garcia M, Doebele RC, Covington KR, Hampton OA, Doddapaneni HV, Jayaseelan JC, Hu J, Wheeler DA, Shay JW, Rimm DL, Gazdar A, Minna JD. Non-malignant respiratory epithelial cells preferentially proliferate from resected non-small cell lung cancer specimens cultured under conditionally reprogrammed conditions. Oncotarget. 2017 Feb;8(7):11114-11126. Pubmedid: 28052041. Pmcid: PMC5355251.
  • Jhuraney A, Woods NT, Wright G, Rix L, Kinose F, Kroeger JL, Remily-Wood E, Cress WD, Koomen JM, Brantley SG, Gray JE, Haura EB, Rix U, Monteiro AN. PAXIP1 Potentiates the Combination of WEE1 Inhibitor AZD1775 and Platinum Agents in Lung Cancer. Mol Cancer Ther. 2016 Jul;15(7):1669-1681. Pubmedid: 27196765. Pmcid: PMC4936941.
  • Peter B, Winter GE, Blatt K, Bennett KL, Stefanzl G, Rix U, Eisenwort G, Hadzijusufovic E, Gridling M, Dutreix C, Hoermann G, Schwaab J, Radia D, Roesel J, Manley PW, Reiter A, Superti-Furga G, Valent P. Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth. Leukemia. 2016 Feb;30(2):464-472. Pubmedid: 26349526. Pmcid: PMC4896384.
  • Li J, Fang B, Kinose F, Bai Y, Kim JY, Chen YA, Rix U, Koomen JM, Haura EB. Target Identification in Small Cell Lung Cancer via Integrated Phenotypic Screening and Activity-Based Protein Profiling. Mol Cancer Ther. 2016 Feb;15(2):334-342. Pubmedid: 26772203. Pmcid: PMC4747823.
  • Knezevic CE, Wright G, Remsing Rix LL, Kim W, Kuenzi BM, Luo Y, Watters JM, Koomen JM, Haura EB, Monteiro AN, Radu C, Lawrence HR, Rix U. Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets. Cell Chem Biol. 2016 Dec;23(12):1490-1503. Pubmedid: 27866910. Pmcid: PMC5182133.
  • Kuenzi BM, Borne AL, Li J, Haura EB, Eschrich SA, Koomen JM, Rix U, Stewart PA. APOSTL: An Interactive Galaxy Pipeline for Reproducible Analysis of Affinity Proteomics Data. J Proteome Res. 2016 Dec;15(12):4747-4754. Pubmedid: 27680298. Pmcid: PMC5231908.
  • Fang B, Hoffman MA, Mirza AS, Mishall KM, Li J, Peterman SM, Smalley KS, Shain KH, Weinberger PM, Wu J, Rix U, Haura EB, Koomen JM. Evaluating kinase ATP uptake and tyrosine phosphorylation using multiplexed quantification of chemically labeled and post-translationally modified peptides. Methods. 2015 Jun;81:41-49. Pubmedid: 25782629. Pmcid: PMC4460980.
  • Haura EB, Beg AA, Rix U, Antonia S. Charting Immune Signaling Proteomes En Route to New Therapeutic Strategies. Cancer Immunol Res. 2015 Jul;3(7):714-720. Pubmedid: 26081226. Pmcid: PMC4491034.
  • Muellner MK, Mair B, Ibrahim Y, Kerzendorfer C, Lechtermann H, Trefzer C, Klepsch F, Müller AC, Leitner E, Macho-Maschler S, Superti-Furga G, Bennett KL, Baselga J, Rix U, Kubicek S, Colinge J, Serra V, Nijman SM. Targeting a cell state common to triple-negative breast cancers. Mol Syst Biol. 2015 Feb;11(1):789. Pubmedid: 25699542. Pmcid: PMC4358660.
  • Sumi NJ, Kuenzi BM, Knezevic CE, Remsing Rix LL, Rix U. Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer. Acs Chem Biol. 2015 Dec;10(12):2680-2686. Pubmedid: 26390342. Pmcid: PMC4684772.
  • Haura EB, Rix U. Deploying ibrutinib to lung cancer: another step in the quest towards drug repurposing. J Natl Cancer Inst. 2014 Sep;106(9). Pubmedid: 25214562. Pmcid: PMC5072366.
  • Gridling M, Ficarro S, Breitwieser FP, Song L, Parapatics K, Colinge J, Haura EB, Marto J, Superti-Furga G, Bennett KL, Rix U. Identification of kinase inhibitor targets in the lung cancer microenvironment by chemical and phosphoproteomics. Mol Cancer Ther. 2014 Nov;13(11):2751-2762. Pubmedid: 25189542. Pmcid: PMC4221415.
  • Yang H, Lawrence HR, Kazi A, Gevariya H, Patel R, Luo Y, Rix U, Schonbrunn E, Lawrence NJ, Sebti SM. Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation. Oncotarget. 2014 May;5(10):2947-2961. Pubmedid: 24930769. Pmcid: PMC4102782.
  • Borgdorff V, Rix U, Winter GE, Gridling M, Müller AC, Breitwieser FP, Wagner C, Colinge J, Bennett KL, Superti-Furga G, Wagner SN. A chemical biology approach identifies AMPK as a modulator of melanoma oncogene MITF. Oncogene. 2014 May;33(19):2531-9. Pubmedid: 23728343.
  • Remsing Rix LL, Kuenzi BM, Luo Y, Remily-Wood E, Kinose F, Wright G, Li J, Koomen JM, Haura EB, Lawrence HR, Rix U. GSK3 alpha and beta are new functionally relevant targets of tivantinib in lung cancer cells. Acs Chem Biol. 2014 Feb;9(2):353-358. Pubmedid: 24215125. Pmcid: PMC3944088.
  • Bai Y, Kim JY, Watters JM, Fang B, Kinose F, Song L, Koomen JM, Teer JK, Fisher K, Chen YA, Rix U, Haura EB. Adaptive responses to dasatinib-treated lung squamous cell cancer cells harboring DDR2 mutations. Cancer Res. 2014 Dec;74(24):7217-7228. Pubmedid: 25348954. Pmcid: PMC4326029.
  • Chamrád I, Rix U, Stukalov A, Gridling M, Parapatics K, Müller AC, Altiok S, Colinge J, Superti-Furga G, Haura EB, Bennett KL. A miniaturized chemical proteomic approach for target profiling of clinical kinase inhibitors in tumor biopsies. J Proteome Res. 2013 Sep;12(9):4005-4017. Pubmedid: 23901793. Pmcid: PMC4127982.
  • Rix U, Colinge J, Blatt K, Gridling M, Remsing Rix LL, Parapatics K, Cerny-Reiterer S, Burkard TR, Jäger U, Melo JV, Bennett KL, Valent P, Superti-Furga G. A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL. PLoS One. 2013 Oct;8(10):e77155. Pubmedid: 24130846. Pmcid: PMC3795025.
  • Li J, Bennett K, Stukalov A, Fang B, Zhang G, Yoshida T, Okamoto I, Kim JY, Song L, Bai Y, Qian X, Rawal B, Schell M, Grebien F, Winter G, Rix U, Eschrich S, Colinge J, Koomen J, Superti-Furga G, Haura EB. Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms. Mol Syst Biol. 2013 Nov;9:705. Pubmedid: 24189400. Pmcid: PMC4039310.
  • Kim JY, Welsh EA, Oguz U, Fang B, Bai Y, Kinose F, Bronk C, Remsing Rix LL, Beg AA, Rix U, Eschrich SA, Koomen JM, Haura EB. Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells. Proc Natl Acad Sci U S A. 2013 Jul;110(30):12414-12419. Pubmedid: 23836654. Pmcid: PMC3725062.
  • Winter GE, Rix U, Carlson SM, Gleixner KV, Grebien F, Gridling M, Müller AC, Breitwieser FP, Bilban M, Colinge J, Valent P, Bennett KL, White FM, Superti-Furga G. Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. Nat Chem Biol. 2012 Nov;8(11):905-912. Pubmedid: 23023260. Pmcid: PMC4038039.
  • Brandt O, Mildner M, Egger AE, Groessl M, Rix U, Posch M, Keppler BK, Strupp C, Mueller B, Stingl G. Nanoscalic silver possesses broad-spectrum antimicrobial activities and exhibits fewer toxicological side effects than silver sulfadiazine. Nanomedicine. 2012 May;8(4):478-488. Pubmedid: 21839058.
  • Rix U, Gridling M, Superti-Furga G. Compound immobilization and drug-affinity chromatography. Methods Mol Biol. 2012 Mar;803:25-38. Pubmedid: 22065216.
  • Colinge J, Rix U, Bennett KL, Superti-Furga G. Systems biology analysis of protein-drug interactions. Proteom Clin Appl. 2012 Jan;6(1-2):102-116. Pubmedid: 22213655.
  • Winter GE, Rix U, Lissat A, Stukalov A, Müllner MK, Bennett KL, Colinge J, Nijman SM, Kubicek S, Kovar H, Kontny U, Superti-Furga G. An integrated chemical biology approach identifies specific vulnerability of Ewing's sarcoma to combined inhibition of Aurora kinases A and B. Mol Cancer Ther. 2011 Oct;10(10):1846-1856. Pubmedid: 21768330.
  • Gleixner KV, Mayerhofer M, Cerny-Reiterer S, Hörmann G, Rix U, Bennett KL, Hadzijusufovic E, Meyer RA, Pickl WF, Gotlib J, Horny HP, Reiter A, Mitterbauer-Hohendanner G, Superti-Furga G, Valent P. KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib. Blood. 2011 Aug;118(7):1885-1898. Pubmedid: 21680801.
  • Kim LC, Rix U, Haura EB. Dasatinib in solid tumors. Expert Opin Inv Drug. 2010 Mar;19(3):415-425. Pubmedid: 20113198.
  • Burkard TR, Rix U, Breitwieser FP, Superti-Furga G, Colinge J. A computational approach to analyze the mechanism of action of the kinase inhibitor bafetinib. PLoS Comput Biol. 2010 Mar;6(11):e1001001. Pubmedid: 21124949. Pmcid: PMC2987840.
  • Ubaida Mohien C, Hartler J, Breitwieser F, Rix U, Remsing Rix L, Winter GE, Thallinger GG, Bennett KL, Superti-Furga G, Trajanoski Z, Colinge J. MASPECTRAS 2: An integration and analysis platform for proteomic data. Proteomics. 2010 Jul;10(14):2719-2722. Pubmedid: 20455215.
  • Rix U, Remsing Rix LL, Terker AS, Fernbach NV, Hantschel O, Planyavsky M, Breitwieser FP, Herrmann H, Colinge J, Bennett KL, Augustin M, Till JH, Heinrich MC, Valent P, Superti-Furga G. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia. 2010 Jan;24(1):44-50. Pubmedid: 19890374.
  • Li J, Rix U, Fang B, Bai Y, Edwards A, Colinge J, Bennett KL, Gao J, Song L, Eschrich S, Superti-Furga G, Koomen J, Haura EB. A chemical and phosphoproteomic characterization of dasatinib action in lung cancer. Nat Chem Biol. 2010 Apr;6(4):291-299. Pubmedid: 20190765. Pmcid: PMC2842457.
  • Rix U, Superti-Furga G. Target profiling of small molecules by chemical proteomics. Nat Chem Biol. 2009 Sep;5(9):616-624. Pubmedid: 19690537.
  • Fernbach NV, Planyavsky M, Müller A, Breitwieser FP, Colinge J, Rix U, Bennett KL. Acid elution and one-dimensional shotgun analysis on an Orbitrap mass spectrometer: an application to drug affinity chromatography. J Proteome Res. 2009 Oct;8(10):4753-4765. Pubmedid: 19653696.
  • Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-485. Pubmedid: 19039322.
  • Sillaber C, Herrmann H, Bennett K, Rix U, Baumgartner C, Böhm A, Herndlhofer S, Tschachler E, Superti-Furga G, Jäger U, Valent P. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest. 2009 Dec;39(12):1098-1109. Pubmedid: 19744184.
  • Kneidinger M, Schmidt U, Rix U, Gleixner KV, Vales A, Baumgartner C, Lupinek C, Weghofer M, Bennett KL, Herrmann H, Schebesta A, Thomas WR, Vrtala S, Valenta R, Lee FY, Ellmeier W, Superti-Furga G, Valent P. The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar;111(6):3097-3107. Pubmedid: 18180381.
  • Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma. 2008 Apr;49(4):615-619. Pubmedid: 18398720.
  • Schuster C, Fernbach N, Rix U, Superti-Furga G, Holy M, Freissmuth M, Sitte HH, Sexl V. Selective serotonin reuptake inhibitors--a new modality for the treatment of lymphoma/leukaemia?. Biochem Pharmacol. 2007 Nov;74(9):1424-1435. Pubmedid: 17709099.
  • Rix U, Hantschel O, Dürnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, Kaupe I, Bennett KL, Valent P, Colinge J, Köcher T, Superti-Furga G. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007 Dec;110(12):4055-4063. Pubmedid: 17720881.
  • Hantschel O, Rix U, Schmidt U, Bürckstümmer T, Kneidinger M, Schütze G, Colinge J, Bennett KL, Ellmeier W, Valent P, Superti-Furga G. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci U S A. 2007 Aug;104(33):13283-13288. Pubmedid: 17684099. Pmcid: PMC1940229.
  • Rix U, Wang C, Chen Y, Lipata FM, Remsing Rix LL, Greenwell LM, Vining LC, Yang K, Rohr J. The oxidative ring cleavage in jadomycin biosynthesis: a multistep oxygenation cascade in a biosynthetic black box. Chembiochem. 2005 May;6(5):838-845. Pubmedid: 15776503.
  • Zheng JT, Rix U, Zhao L, Mattingly C, Adams V, Chen Q, Rohr J, Yang KQ. Cytotoxic activities of new jadomycin derivatives. J Antibiot. 2005 Jun;58(6):405-408. Pubmedid: 16156517. Pmcid: PMC2881663.
  • Chen YH, Wang CC, Greenwell L, Rix U, Hoffmeister D, Vining LC, Rohr J, Yang KQ. Functional analyses of oxygenases in jadomycin biosynthesis and identification of JadH as a bifunctional oxygenase/dehydrase. J Biol Chem. 2005 Jun;280(23):22508-22514. Pubmedid: 15817470. Pmcid: PMC2883817.
  • Zhu L, Ostash B, Rix U, Nur-E-Alam M, Mayers A, Luzhetskyy A, Mendez C, Salas JA, Bechthold A, Fedorenko V, Rohr J. Identification of the function of gene lndM2 encoding a bifunctional oxygenase-reductase involved in the biosynthesis of the antitumor antibiotic landomycin E by Streptomyces globisporus 1912 supports the originally assigned structure for landomycinone. J Org Chem. 2005 Jan;70(2):631-638. Pubmedid: 15651811. Pmcid: PMC2884283.
  • Rix U, Zheng J, Remsing Rix LL, Greenwell L, Yang K, Rohr J. The dynamic structure of jadomycin B and the amino acid incorporation step of its biosynthesis. J Am Chem Soc. 2004 Apr;126(14):4496-4497. Pubmedid: 15070349.
  • Ostash B, Rix U, Rix LL, Liu T, Lombo F, Luzhetskyy A, Gromyko O, Wang C, Braña AF, Méndez C, Salas JA, Fedorenko V, Rohr J. Generation of new landomycins by combinatorial biosynthetic manipulation of the LndGT4 gene of the landomycin E cluster in S. globisporus. Chem Biol. 2004 Apr;11(4):547-555. Pubmedid: 15123249.
  • Remsing LL, González AM, Nur-e-Alam M, Fernández-Lozano MJ, Braña AF, Rix U, Oliveira MA, Méndez C, Salas JA, Rohr J. Mithramycin SK, a novel antitumor drug with improved therapeutic index, mithramycin SA, and demycarosyl-mithramycin SK: three new products generated in the mithramycin producer Streptomyces argillaceus through combinatorial biosynthesis. J Am Chem Soc. 2003 May;125(19):5745-5753. Pubmedid: 12733914. Pmcid: PMC4480629.
  • Rix U, Remsing LL, Hoffmeister D, Bechthold A, Rohr J. Urdamycin L: a novel metabolic shunt product that provides evidence for the role of the urdM gene in the urdamycin A biosynthetic pathway of Streptomyces fradiae TU 2717. Chembiochem. 2003 Jan;4(1):109-111. Pubmedid: 12512084.
  • Rix U, Fischer C, Remsing LL, Rohr J. Modification of post-PKS tailoring steps through combinatorial biosynthesis. Nat Prod Rep. 2002 Oct;19(5):542-580. Pubmedid: 12430723.
  • Trefzer A, Blanco G, Remsing L, Künzel E, Rix U, Lipata F, Braña AF, Méndez C, Rohr J, Bechthold A, Salas JA. Rationally designed glycosylated premithramycins: hybrid aromatic polyketides using genes from three different biosynthetic pathways. J Am Chem Soc. 2002 May;124(21):6056-6062. Pubmedid: 12022840.
  • Remsing LL, Garcia-Bernardo J, Gonzalez A, Künzel E, Rix U, Braña AF, Bearden DW, Méndez C, Salas JA, Rohr J. Ketopremithramycins and ketomithramycins, four new aureolic acid-type compounds obtained upon inactivation of two genes involved in the biosynthesis of the deoxysugar moieties of the antitumor drug mithramycin by Streptomyces argillaceus, reveal novel ins. J Am Chem Soc. 2002 Feb;124(8):1606-1614. Pubmedid: 11853433. Pmcid: PMC4480631.
  • Macky TA, Oelkers C, Rix U, Heredia ML, Künzel E, Wimberly M, Rohrer B, Crosson CE, Rohr J. Synthesis, pharmacokinetics, efficacy, and rat retinal toxicity of a novel mitomycin C-triamcinolone acetonide conjugate. J Med Chem. 2002 Feb;45(5):1122-1127. Pubmedid: 11855992.
  • Trefzer A, Hoffmeister D, Künzel E, Stockert S, Weitnauer G, Westrich L, Rix U, Fuchser J, Bindseil KU, Rohr J, Bechthold A. Function of glycosyltransferase genes involved in urdamycin A biosynthesis. Chem Biol. 2000 Feb;7(2):133-142. Pubmedid: 10662691.