Dr Ultan McDermott | CDF Group Leader

Ultan McDermott is a clinician scientist and has a lifelong interest in understanding how cancer genomes affect response in the clinic to therapy, and in particular the use of genetic screens to identify mechanisms of drug resistance in cancer.

At the Sanger Institute we have created a platform to enable high-throughput drug screens in one of the largest and best annotated collections of cancer cell lines. This has enabled us to systematically identify genomic alterations associated with drug sensitivity for hundreds of clinical and pre-clinical agents. This should facilitate the rational design of clinical trials that stratify patients for treatment based upon such alterations.

However, despite an increasing array of new cancer therapies, drug resistance is an almost universal phenomenon. The emergence of drug resistance ultimately proves fatal for the majority of patients, and therefore the early detection of resistance and the identification of novel strategies to overcome the underlying mechanisms is a subject of intense activity world-wide. I have therefore begun to develop a programme to systematically identify the landscape of resistance mutations for all clinical therapies using the Sanger’s collection of 1,001 cancer cell lines and that includes targeted agents, chemotherapeutics and radiotherapy. This programme takes advantage of recent advances in genetic screen technologies, including CRISPR/Cas9, to interrogate the entire cancer genome for its potential to confer drug resistance. Once identified, we will use both high-throughput chemical screens as well as CRISPR/Cas9 lethality screens to identify ways to overcome drug resistance and potentially discover second-line therapies to use with such patients in the clinic. 

Ultan joined the Sanger Institute in 2009 as a clinical research fellow and was appointed to the faculty as a CDF Group Leader in 2010 with the award of a Cancer Research UK Clinician Scientist Fellowship. Previously he worked as a postdoctoral fellow with Jeff Settleman at Massachusetts General Hospital Cancer Center on high-throughput cancer cell line drug screens and resistance mechanisms. He is a Fellow of the Royal College of Physicians.

Publications

  • Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations.

    Brammeld JS, Petljak M, Martincorena I, Williams SP, Alonso LG et al.

    Genome research 2017

  • A Landscape of Pharmacogenomic Interactions in Cancer.

    Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP et al.

    Cell 2016;166;3;740-54

  • FANCD2 limits replication stress and genome instability in cells lacking BRCA2.

    Michl J, Zimmer J, Buffa FM, McDermott U and Tarsounas M

    Nature structural & molecular biology 2016;23;8;755-7

  • Prospective derivation of a living organoid biobank of colorectal cancer patients.

    van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F et al.

    Cell 2015;161;4;933-45

  • Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.

    Vizoso M, Ferreira HJ, Lopez-Serra P, Carmona FJ, Martínez-Cardús A et al.

    Nature medicine 2015;21;7;741-50

  • The evolutionary history of lethal metastatic prostate cancer.

    Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM et al.

    Nature 2015;520;7547;353-7

  • Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

    Cooper CS, Eeles R, Wedge DC, Van Loo P, Gundem G et al.

    Nature genetics 2015;47;4;367-72

  • Inactivating CUX1 mutations promote tumorigenesis.

    Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C et al.

    Nature genetics 2014;46;1;33-8

  • MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.

    Huang S, Hölzel M, Knijnenburg T, Schlicker A, Roepman P et al.

    Cell 2012;151;5;937-50

  • Systematic identification of genomic markers of drug sensitivity in cancer cells.

    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A et al.

    Nature 2012;483;7391;570-5

  • Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations.

    Brammeld JS, Petljak M, Martincorena I, Williams SP, Alonso LG et al.

    Genome research 2017

  • Logic models to predict continuous outputs based on binary inputs with an application to personalized cancer therapy.

    Knijnenburg TA, Klau GW, Iorio F, Garnett MJ, McDermott U et al.

    Scientific reports 2016;6;36812

  • A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia.

    Tzelepis K, Koike-Yusa H, De Braekeleer E, Li Y, Metzakopian E et al.

    Cell reports 2016;17;4;1193-1205

  • A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation.

    Kollmann K, Warsch W, Gonzalez-Arias C, Nice FL, Avezov E et al.

    Leukemia 2016

  • Mutational signatures of ionizing radiation in second malignancies.

    Behjati S, Gundem G, Wedge DC, Roberts ND, Tarpey PS et al.

    Nature communications 2016;7;12605

  • FANCD2 limits replication stress and genome instability in cells lacking BRCA2.

    Michl J, Zimmer J, Buffa FM, McDermott U and Tarsounas M

    Nature structural & molecular biology 2016;23;8;755-7

  • A Landscape of Pharmacogenomic Interactions in Cancer.

    Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP et al.

    Cell 2016;166;3;740-54

  • BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts.

    Kemper K, Krijgsman O, Kong X, Cornelissen-Steijger P, Shahrabi A et al.

    Cell reports 2016;16;1;263-77

  • Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC-dependence in intrahepatic cholangiocarcinoma.

    Saha SK, Gordan JD, Kleinstiver BP, Vu P, Najem MS et al.

    Cancer discovery 2016

  • Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.

    Ham J, Costa C, Sano R, Lochmann TL, Sennott EM et al.

    Cancer cell 2016;29;2;159-72

  • Pharmacogenomic agreement between two cancer cell line data sets.

    Cancer Cell Line Encyclopedia Consortium and Genomics of Drug Sensitivity in Cancer Consortium

    Nature 2015;528;7580;84-7

  • Next-generation sequencing and empowering personalised cancer medicine.

    McDermott U

    Drug discovery today 2015;20;12;1470-5

  • LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation.

    Mardilovich K, Baugh M, Crighton D, Kowalczyk D, Gabrielsen M et al.

    Oncotarget 2015;6;36;38469-86

  • Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells.

    Hearn JM, Romero-Canelón I, Munro AF, Fu Y, Pizarro AM et al.

    Proceedings of the National Academy of Sciences of the United States of America 2015;112;29;E3800-5

  • Analysis of mutational signatures in exomes from B-cell lymphoma cell lines suggest APOBEC3 family members to be involved in the pathogenesis of primary effusion lymphoma.

    Wagener R, Alexandrov LB, Montesinos-Rongen M, Schlesner M, Haake A et al.

    Leukemia 2015;29;7;1612-5

  • Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.

    Vizoso M, Ferreira HJ, Lopez-Serra P, Carmona FJ, Martínez-Cardús A et al.

    Nature medicine 2015;21;7;741-50

  • Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.

    Ju YS, Tubio JM, Mifsud W, Fu B, Davies HR et al.

    Genome research 2015;25;6;814-24

  • The evolutionary history of lethal metastatic prostate cancer.

    Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM et al.

    Nature 2015;520;7547;353-7

  • Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

    Cooper CS, Eeles R, Wedge DC, Van Loo P, Gundem G et al.

    Nature genetics 2015;47;4;367-72

  • Mutation detection in formalin-fixed prostate cancer biopsies taken at the time of diagnosis using next-generation DNA sequencing.

    Manson-Bahr D, Ball R, Gundem G, Sethia K, Mills R et al.

    Journal of clinical pathology 2015;68;3;212-7

  • BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib.

    Ranzani M, Alifrangis C, Perna D, Dutton-Regester K, Pritchard A et al.

    Pigment cell & melanoma research 2015;28;1;117-9

  • Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.

    Gill SJ, Travers J, Pshenichnaya I, Kogera FA, Barthorpe S et al.

    PloS one 2015;10;10;e0140988

  • COSMIC: exploring the world's knowledge of somatic mutations in human cancer.

    Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N et al.

    Nucleic acids research 2015;43;Database issue;D805-11

  • Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.

    Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S et al.

    eLife 2014;3

  • Reading between the lines; understanding drug response in the post genomic era.

    Alifrangis CC and McDermott U

    Molecular oncology 2014;8;6;1112-9

  • Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes.

    Tubio JM, Li Y, Ju YS, Martincorena I, Cooke SL et al.

    Science (New York, N.Y.) 2014;345;6196;1251343

  • Processed pseudogenes acquired somatically during cancer development.

    Cooke SL, Shlien A, Marshall J, Pipinikas CP, Martincorena I et al.

    Nature communications 2014;5;3644

  • Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

    Behjati S, Tarpey PS, Sheldon H, Martincorena I, Van Loo P et al.

    Nature genetics 2014;46;4;376-9

  • The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response.

    Garnett MJ and McDermott U

    Current opinion in genetics & development 2014;24;114-9

  • Editorial overview: cancer genomics: kill it. Kill it dead.

    Adams D and McDermott U

    Current opinion in genetics & development 2014;24;v-vi

  • A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect.

    Lopez-Serra P, Marcilla M, Villanueva A, Ramos-Fernandez A, Palau A et al.

    Nature communications 2014;5;3608

  • Inactivating CUX1 mutations promote tumorigenesis.

    Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C et al.

    Nature genetics 2014;46;1;33-8

  • Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

    Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W et al.

    Nature communications 2014;5;5712

  • Signatures of mutational processes in human cancer.

    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S et al.

    Nature 2013;500;7463;415-21

  • A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.

    Rad R, Cadiñanos J, Rad L, Varela I, Strong A et al.

    Cancer cell 2013;24;1;15-29

  • Whole exome sequencing of adenoid cystic carcinoma.

    Stephens PJ, Davies HR, Mitani Y, Van Loo P, Shlien A et al.

    The Journal of clinical investigation 2013;123;7;2965-8

  • Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.

    He L, Torres-Lockhart K, Forster N, Ramakrishnan S, Greninger P et al.

    Cancer discovery 2013;3;3;324-37

  • Targeting MYCN in neuroblastoma by BET bromodomain inhibition.

    Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J et al.

    Cancer discovery 2013;3;3;308-23

  • VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.

    Hart S, Novotny-Diermayr V, Goh KC, Williams M, Tan YC et al.

    Molecular cancer therapeutics 2013;12;2;151-61

  • Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells.

    Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H et al.

    Nucleic acids research 2013;41;Database issue;D955-61

  • MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.

    Huang S, Hölzel M, Knijnenburg T, Schlicker A, Roepman P et al.

    Cell 2012;151;5;937-50

  • A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.

    Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F et al.

    Cell 2010;141;1;69-80

  • Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency.

    McDermott U, Pusapati RV, Christensen JG, Gray NS and Settleman J

    Cancer research 2010;70;4;1625-34

  • Personalized cancer therapy with selective kinase inhibitors: an emerging paradigm in medical oncology.

    McDermott U and Settleman J

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009;27;33;5650-9

  • Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors.

    McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M et al.

    Cancer research 2008;68;9;3389-95

  • Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling.

    McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C et al.

    Proceedings of the National Academy of Sciences of the United States of America 2007;104;50;19936-41

Career/Research Highlights

McDermott, Ultan
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Ultan's Timeline
2011

Appointed as Fellow of Royal College of Physicians.

2010

Awarded CRUK Clinician Scientist Fellowship.

Career Development Fellow Group Leader at Sanger Institute.

2009

Joined Wellcome Trust Sanger Institute as clinical research fellow in the Cancer Genome Project.

Honorary Consultant Medical Oncologist at Addenbrooke's Hospital, Cambridge.

2005

Posdoctoral fellowship with Jeff Settleman at Massachusetts General Hospital Cancer Center, Boston.

PhD - Queen's University Belfast.

2003

Completion of Specialist Training in Medical Oncology (UK)

1994

Graduated Medical School - Queen's University Belfast.

1992

BMedSci with Honours - Queen's University Belfast.