Now showing items 1-20 of 21

    • ATR Is a Therapeutic Target in Synovial Sarcoma. 

      Jones, SE; Fleuren, EDG; Frankum, J; Konde, A; Williamson, CT; Krastev, DB; Pemberton, HN; Campbell, J; Gulati, A; Elliott, R; Menon, M; Selfe, JL; Brough, R; Pettitt, SJ; Niedzwiedz, W; van der Graaf, WTA; Shipley, J; Ashworth, A; Lord, CJ (2017-12)
      Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we ...
    • Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. 

      Carreira, S; Porta, N; Arce-Gallego, S; Seed, G; Llop-Guevara, A; Bianchini, D; Rescigno, P; Paschalis, A; Bertan, C; Baker, C; Goodall, J; Miranda, S; Riisnaes, R; Figueiredo, I; Ferreira, A; Pereira, R; Crespo, M; Gurel, B; Nava Rodrigues, D; Pettitt, SJ; Yuan, W; Serra, V; Rekowski, J; Lord, CJ; Hall, E; Mateo, J; de Bono, JS (2021-05-27)
      PARP inhibitors are approved for treating advanced prostate cancers (APCs) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed ...
    • Chemosensitivity profiling of osteosarcoma tumour cell lines identifies a model of BRCAness. 

      Holme, H; Gulati, A; Brough, R; Fleuren, EDG; Bajrami, I; Campbell, J; Chong, IY; Costa-Cabral, S; Elliott, R; Fenton, T; Frankum, J; Jones, SE; Menon, M; Miller, R; Pemberton, HN; Postel-Vinay, S; Rafiq, R; Selfe, JL; von Kriegsheim, A; Munoz, AG; Rodriguez, J; Shipley, J; van der Graaf, WTA; Williamson, CT; Ryan, CJ; Pettitt, S; Ashworth, A; Strauss, SJ; Lord, CJ (2018-07-13)
      Osteosarcoma (OS) is an aggressive sarcoma, where novel treatment approaches are required. Genomic studies suggest that a subset of OS, including OS tumour cell lines (TCLs), exhibit genomic loss of heterozygosity (LOH) ...
    • Clinical <i>BRCA1/2</i> Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance. 

      Pettitt, SJ; Frankum, JR; Punta, M; Lise, S; Alexander, J; Chen, Y; Yap, TA; Haider, S; Tutt, ANJ; Lord, CJ (2020-10)
      Reversion mutations in <i>BRCA1</i> or <i>BRCA2</i> are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 ...
    • Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets. 

      Krastev, DB; Pettitt, SJ; Campbell, J; Song, F; Tanos, BE; Stoynov, SS; Ashworth, A; Lord, CJ (2018-05-22)
      Poly (ADP-ribose)ylation is a dynamic protein modification that regulates multiple cellular processes. Here, we describe a system for identifying and characterizing PARylation events that exploits the ability of a PBZ ...
    • Dissecting PARP inhibitor resistance with functional genomics. 

      Pettitt, SJ; Lord, CJ (2019-02)
      The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. ...
    • E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer. 

      Bajrami, I; Marlow, R; van de Ven, M; Brough, R; Pemberton, HN; Frankum, J; Song, F; Rafiq, R; Konde, A; Krastev, DB; Menon, M; Campbell, J; Gulati, A; Kumar, R; Pettitt, SJ; Gurden, MD; Cardenosa, ML; Chong, I; Gazinska, P; Wallberg, F; Sawyer, EJ; Martin, L-A; Dowsett, M; Linardopoulos, S; Natrajan, R; Ryan, CJ; Derksen, PWB; Jonkers, J; Tutt, ANJ; Ashworth, A; Lord, CJ (2018-04)
      The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells ...
    • Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells. 

      Nikkilä, J; Kumar, R; Campbell, J; Brandsma, I; Pemberton, HN; Wallberg, F; Nagy, K; Scheer, I; Vertessy, BG; Serebrenik, AA; Monni, V; Harris, RS; Pettitt, SJ; Ashworth, A; Lord, CJ (2017-06)
      Elevated APOBEC3B expression in tumours correlates with a kataegic pattern of localised hypermutation. We assessed the cellular phenotypes associated with high-level APOBEC3B expression and the influence of p53 status on ...
    • Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. 

      Pettitt, SJ; Krastev, DB; Brandsma, I; Dréan, A; Song, F; Aleksandrov, R; Harrell, MI; Menon, M; Brough, R; Campbell, J; Frankum, J; Ranes, M; Pemberton, HN; Rafiq, R; Fenwick, K; Swain, A; Guettler, S; Lee, J-M; Swisher, EM; Stoynov, S; Yusa, K; Ashworth, A; Lord, CJ (2018-05-10)
      Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 ...
    • Genome-wide barcoded transposon screen for cancer drug sensitivity in haploid mouse embryonic stem cells. 

      Pettitt, SJ; Krastev, DB; Pemberton, HN; Fontebasso, Y; Frankum, J; Rehman, FL; Brough, R; Song, F; Bajrami, I; Rafiq, R; Wallberg, F; Kozarewa, I; Fenwick, K; Armisen-Garrido, J; Swain, A; Gulati, A; Campbell, J; Ashworth, A; Lord, CJ (2017-03)
      We describe a screen for cellular response to drugs that makes use of haploid embryonic stem cells. We generated ten libraries of mutants with piggyBac gene trap transposon integrations, totalling approximately 100,000 ...
    • Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer. 

      Brough, R; Gulati, A; Haider, S; Kumar, R; Campbell, J; Knudsen, E; Pettitt, SJ; Ryan, CJ; Lord, CJ (2018-10)
      Although defects in the RB1 tumour suppressor are one of the more common driver alterations found in triple-negative breast cancer (TNBC), therapeutic approaches that exploit this have not been identified. By integrating ...
    • Longitudinal analysis of a secondary BRCA2 mutation using digital droplet PCR. 

      Khalique, S; Pettitt, SJ; Kelly, G; Tunariu, N; Natrajan, R; Banerjee, S; Lord, CJ (2020-01)
      Development of resistance to platinum and poly(ADP-ribose) polymerase inhibitors via secondary BRCA gene mutations that restore functional homologous recombination has been observed in a number of cancer types. Here we ...
    • Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer. 

      Chong, IY; Aronson, L; Bryant, H; Gulati, A; Campbell, J; Elliott, R; Pettitt, S; Wilkerson, P; Lambros, MB; Reis-Filho, JS; Ramessur, A; Davidson, M; Chau, I; Cunningham, D; Ashworth, A; Lord, CJ (2018-10)
      Objective Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.Design To identify new biomarker-defined therapeutic approaches ...
    • Modeling Therapy Resistance in <i>BRCA1/2</i>-Mutant Cancers. 

      Dréan, A; Williamson, CT; Brough, R; Brandsma, I; Menon, M; Konde, A; Garcia-Murillas, I; Pemberton, HN; Frankum, J; Rafiq, R; Badham, N; Campbell, J; Gulati, A; Turner, NC; Pettitt, SJ; Ashworth, A; Lord, CJ (2017-09)
      Although PARP inhibitors target <i>BRCA1</i>- or <i>BRCA2</i>-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in ...
    • PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer. 

      Chabanon, RM; Muirhead, G; Krastev, DB; Adam, J; Morel, D; Garrido, M; Lamb, A; Hénon, C; Dorvault, N; Rouanne, M; Marlow, R; Bajrami, I; Cardeñosa, ML; Konde, A; Besse, B; Ashworth, A; Pettitt, SJ; Haider, S; Marabelle, A; Tutt, AN; Soria, J-C; Lord, CJ; Postel-Vinay, S (2019-03)
      The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA ...
    • PARP inhibitors and breast cancer: highlights and hang-ups 

      Pettitt, SJ; Lord, CJ (TAYLOR & FRANCIS LTD, 2018-01-01)
    • Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with <i>BRCA1/2</i>- and Non-<i>BRCA1/2</i>-Mutant Cancers. 

      Yap, TA; Kristeleit, R; Michalarea, V; Pettitt, SJ; Lim, JSJ; Carreira, S; Roda, D; Miller, R; Riisnaes, R; Miranda, S; Figueiredo, I; Rodrigues, DN; Ward, S; Matthews, R; Parmar, M; Turner, A; Tunariu, N; Chopra, N; Gevensleben, H; Turner, NC; Ruddle, R; Raynaud, FI; Decordova, S; Swales, KE; Finneran, L; Hall, E; Rugman, P; Lindemann, JPO; Foxley, A; Lord, CJ; Banerji, U; Plummer, R; Basu, B; Lopez, JS; Drew, Y; de Bono, JS (2020-10)
      Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in <i>BRCA1</i> and <i>BRCA2</i> (<i>BRCA1/2)</i>-deficient and <i>BRCA1/2</i>-proficient tumors. We conducted an investigator-initiated ...
    • Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. 

      Zatreanu, D; Robinson, HMR; Alkhatib, O; Boursier, M; Finch, H; Geo, L; Grande, D; Grinkevich, V; Heald, RA; Langdon, S; Majithiya, J; McWhirter, C; Martin, NMB; Moore, S; Neves, J; Rajendra, E; Ranzani, M; Schaedler, T; Stockley, M; Wiggins, K; Brough, R; Sridhar, S; Gulati, A; Shao, N; Badder, LM; Novo, D; Knight, EG; Marlow, R; Haider, S; Callen, E; Hewitt, G; Schimmel, J; Prevo, R; Alli, C; Ferdinand, A; Bell, C; Blencowe, P; Bot, C; Calder, M; Charles, M; Curry, J; Ekwuru, T; Ewings, K; Krajewski, W; MacDonald, E; McCarron, H; Pang, L; Pedder, C; Rigoreau, L; Swarbrick, M; Wheatley, E; Willis, S; Wong, AC; Nussenzweig, A; Tijsterman, M; Tutt, A; Boulton, SJ; Higgins, GS; Pettitt, SJ; Smith, GCM; Lord, CJ (2021-06-17)
      To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ...
    • Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency. 

      Bajrami, I; Walker, C; Krastev, DB; Weekes, D; Song, F; Wicks, AJ; Alexander, J; Haider, S; Brough, R; Pettitt, SJ; Tutt, ANJ; Lord, CJ (2021-11-08)
      PARP enzymes utilise NAD+ as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either BRCA1 or BRCA2. In order to assess whether other genes implicated in NAD+ metabolism ...
    • The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells. 

      Barazas, M; Annunziato, S; Pettitt, SJ; de Krijger, I; Ghezraoui, H; Roobol, SJ; Lutz, C; Frankum, J; Song, FF; Brough, R; Evers, B; Gogola, E; Bhin, J; van de Ven, M; van Gent, DC; Jacobs, JJL; Chapman, R; Lord, CJ; Jonkers, J; Rottenberg, S (2018-05)
      Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration ...