Now showing items 1-20 of 25

    • 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 ...
    • CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours. 

      Costa-Cabral, S; Brough, R; Konde, A; Aarts, M; Campbell, J; Marinari, E; Riffell, J; Bardelli, A; Torrance, C; Lord, CJ; Ashworth, A (2016-01)
      Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent ...
    • Cells Lacking the <i>RB1</i> Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival. 

      Oser, MG; Fonseca, R; Chakraborty, AA; Brough, R; Spektor, A; Jennings, RB; Flaifel, A; Novak, JS; Gulati, A; Buss, E; Younger, ST; McBrayer, SK; Cowley, GS; Bonal, DM; Nguyen, Q-D; Brulle-Soumare, L; Taylor, P; Cairo, S; Ryan, CJ; Pease, EJ; Maratea, K; Travers, J; Root, DE; Signoretti, S; Pellman, D; Ashton, S; Lord, CJ; Barry, ST; Kaelin, WG (2019-02)
      Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating <i>RB1</i> and <i>TP53</i> mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical ...
    • Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy. 

      Faisal, A; Mak, GWY; Gurden, MD; Xavier, CPR; Anderhub, SJ; Innocenti, P; Westwood, IM; Naud, S; Hayes, A; Box, G; Valenti, MR; De Haven Brandon, AK; O'Fee, L; Schmitt, J; Woodward, HL; Burke, R; vanMontfort, RLM; Blagg, J; Raynaud, FI; Eccles, SA; Hoelder, S; Linardopoulos, S (2017-04)
      Background The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents ...
    • Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα<sup>WT</sup> and ERα<sup>MUT</sup> Breast Cancer. 

      Puyang, X; Furman, C; Zheng, GZ; Wu, ZJ; Banka, D; Aithal, K; Agoulnik, S; Bolduc, DM; Buonamici, S; Caleb, B; Das, S; Eckley, S; Fekkes, P; Hao, M-H; Hart, A; Houtman, R; Irwin, S; Joshi, JJ; Karr, C; Kim, A; Kumar, N; Kumar, P; Kuznetsov, G; Lai, WG; Larsen, N; Mackenzie, C; Martin, L-A; Melchers, D; Moriarty, A; Nguyen, T-V; Norris, J; O'Shea, M; Pancholi, S; Prajapati, S; Rajagopalan, S; Reynolds, DJ; Rimkunas, V; Rioux, N; Ribas, R; Siu, A; Sivakumar, S; Subramanian, V; Thomas, M; Vaillancourt, FH; Wang, J; Wardell, S; Wick, MJ; Yao, S; Yu, L; Warmuth, M; Smith, PG; Zhu, P; Korpal, M (2018-09)
      Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant ...
    • Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. 

      Aarts, M; Sharpe, R; Garcia-Murillas, I; Gevensleben, H; Hurd, MS; Shumway, SD; Toniatti, C; Ashworth, A; Turner, NC (2012-06)
      Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. ...
    • 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 ...
    • High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial. 

      Pearson, A; Smyth, E; Babina, IS; Herrera-Abreu, MT; Tarazona, N; Peckitt, C; Kilgour, E; Smith, NR; Geh, C; Rooney, C; Cutts, R; Campbell, J; Ning, J; Fenwick, K; Swain, A; Brown, G; Chua, S; Thomas, A; Johnston, SRD; Ajaz, M; Sumpter, K; Gillbanks, A; Watkins, D; Chau, I; Popat, S; Cunningham, D; Turner, NC (2016-08)
      Unlabelled FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level ...
    • Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation. 

      Dalton, WB; Helmenstine, E; Walsh, N; Gondek, LP; Kelkar, DS; Read, A; Natrajan, R; Christenson, ES; Roman, B; Das, S; Zhao, L; Leone, RD; Shinn, D; Groginski, T; Madugundu, AK; Patil, A; Zabransky, DJ; Medford, A; Lee, J; Cole, AJ; Rosen, M; Thakar, M; Ambinder, A; Donaldson, J; DeZern, AE; Cravero, K; Chu, D; Madero-Marroquin, R; Pandey, A; Hurley, PJ; Lauring, J; Park, BH (2019-08-08)
      Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are ...
    • HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target. 

      Fok, JHL; Hedayat, S; Zhang, L; Aronson, LI; Mirabella, F; Pawlyn, C; Bright, MD; Wardell, CP; Keats, JJ; De Billy, E; Rye, CS; Chessum, NEA; Jones, K; Morgan, GJ; Eccles, SA; Workman, P; Davies, FE (2018-05)
      Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) ...
    • 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 ...
    • Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation. 

      van Weverwijk, A; Koundouros, N; Iravani, M; Ashenden, M; Gao, Q; Poulogiannis, G; Jungwirth, U; Isacke, CM (2019-06-20)
      The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability ...
    • MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. 

      Lampis, A; Carotenuto, P; Vlachogiannis, G; Cascione, L; Hedayat, S; Burke, R; Clarke, P; Bosma, E; Simbolo, M; Scarpa, A; Yu, S; Cole, R; Smyth, E; Mateos, JF; Begum, R; Hezelova, B; Eltahir, Z; Wotherspoon, A; Fotiadis, N; Bali, MA; Nepal, C; Khan, K; Stubbs, M; Hahne, JC; Gasparini, P; Guzzardo, V; Croce, CM; Eccles, S; Fassan, M; Cunningham, D; Andersen, JB; Workman, P; Valeri, N; Braconi, C (2018-03)
      BACKGROUND & AIMS:Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA ...
    • 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 ...
    • Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. 

      Vlachogiannis, G; Hedayat, S; Vatsiou, A; Jamin, Y; Fernández-Mateos, J; Khan, K; Lampis, A; Eason, K; Huntingford, I; Burke, R; Rata, M; Koh, D-M; Tunariu, N; Collins, D; Hulkki-Wilson, S; Ragulan, C; Spiteri, I; Moorcraft, SY; Chau, I; Rao, S; Watkins, D; Fotiadis, N; Bali, M; Darvish-Damavandi, M; Lote, H; Eltahir, Z; Smyth, EC; Begum, R; Clarke, PA; Hahne, JC; Dowsett, M; de Bono, J; Workman, P; Sadanandam, A; Fassan, M; Sansom, OJ; Eccles, S; Starling, N; Braconi, C; Sottoriva, A; Robinson, SP; Cunningham, D; Valeri, N (2018-02)
      Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from ...
    • Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes. 

      Fleuren, EDG; Vlenterie, M; van der Graaf, WTA; Hillebrandt-Roeffen, MHS; Blackburn, J; Ma, X; Chan, H; Magias, MC; van Erp, A; van Houdt, L; Cebeci, SAS; van de Ven, A; Flucke, UE; Heyer, EE; Thomas, DM; Lord, CJ; Marini, KD; Vaghjiani, V; Mercer, TR; Cain, JE; Wu, J; Versleijen-Jonkers, YMH; Daly, RJ (2017-08)
      Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical ...
    • PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. 

      Brasó-Maristany, F; Filosto, S; Catchpole, S; Marlow, R; Quist, J; Francesch-Domenech, E; Plumb, DA; Zakka, L; Gazinska, P; Liccardi, G; Meier, P; Gris-Oliver, A; Cheang, MCU; Perdrix-Rosell, A; Shafat, M; Noël, E; Patel, N; McEachern, K; Scaltriti, M; Castel, P; Noor, F; Buus, R; Mathew, S; Watkins, J; Serra, V; Marra, P; Grigoriadis, A; Tutt, AN (2016-11)
      Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC ...
    • Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells. 

      Ferraldeschi, R; Welti, J; Powers, MV; Yuan, W; Smyth, T; Seed, G; Riisnaes, R; Hedayat, S; Wang, H; Crespo, M; Nava Rodrigues, D; Figueiredo, I; Miranda, S; Carreira, S; Lyons, JF; Sharp, S; Plymate, SR; Attard, G; Wallis, N; Workman, P; de Bono, JS (2016-05)
      Resistance to available hormone therapies in prostate cancer has been associated with alternative splicing of androgen receptor (AR) and specifically, the expression of truncated and constitutively active AR variant 7 ...
    • Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer. 

      Wagner, S; Vlachogiannis, G; De Haven Brandon, A; Valenti, M; Box, G; Jenkins, L; Mancusi, C; Self, A; Manodoro, F; Assiotis, I; Robinson, P; Chauhan, R; Rust, AG; Matthews, N; Eason, K; Khan, K; Starling, N; Cunningham, D; Sadanandam, A; Isacke, CM; Kirkin, V; Valeri, N; Whittaker, SR (2019-03)
      Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed ...
    • Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma. 

      Beck, D; Zobel, J; Barber, R; Evans, S; Lezina, L; Allchin, RL; Blades, M; Elliott, R; Lord, CJ; Ashworth, A; Porter, ACG; Wagner, SD (2016-08)
      We demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and ...