Browsing Molecular Pathology by author "Lord, Christopher"
Now showing items 41-60 of 81
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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; et al. (NATURE PUBLISHING GROUP, 2018-05-01)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; et al. (NATURE PUBLISHING GROUP, 2017-03-01)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 ... -
Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress.
McDade, SS; Patel, D; Moran, M; Campbell, J; Fenwick, K; et al. (OXFORD UNIV PRESS, 2014-01-01)In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by ... -
HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.
Brunton, H; Caligiuri, G; Cunningham, R; Upstill-Goddard, R; Bailey, U-M; et al. (CELL PRESS, 2020-05-12)Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic ... -
Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer.
Brough, R; Gulati, A; Haider, S; Kumar, R; Campbell, J; et al. (NATURE PUBLISHING GROUP, 2018-10-25)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 ... -
Identifying Genetic Dependencies in Cancer by Analyzing siRNA Screens in Tumor Cell Line Panels.
Campbell, J; Ryan, CJ; Lord, CJ (HUMANA PRESS INC, 2018-01-01)Loss-of-function screening using RNA interference or CRISPR approaches can be used to identify genes that specific tumor cell lines depend upon for survival. By integrating the results from screens in multiple cell lines ... -
Integrative analysis of large-scale loss-of-function screens identifies robust cancer-associated genetic interactions.
Lord, CJ; Quinn, N; Ryan, CJ (ELIFE SCIENCES PUBLICATIONS LTD, 2020-05-28)Genetic interactions, including synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have ... -
Large-Scale Profiling of Kinase Dependencies in Cancer Cell Lines.
Campbell, J; Ryan, CJ; Brough, R; Bajrami, I; Pemberton, HN; et al. (CELL PRESS, 2016-03-15)One approach to identifying cancer-specific vulnerabilities and therapeutic targets is to profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that identify the kinase ... -
Longitudinal analysis of a secondary BRCA2 mutation using digital droplet PCR.
Khalique, S; Pettitt, SJ; Kelly, G; Tunariu, N; Natrajan, R; et al. (WILEY, 2019-11-20)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; et al. (BMJ PUBLISHING GROUP, 2018-10-01)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 BRCA1/2-Mutant Cancers.
Dréan, A; Williamson, CT; Brough, R; Brandsma, I; Menon, M; et al. (AMER ASSOC CANCER RESEARCH, 2017-09-01)Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 ... -
MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma.
King, D; Li, XD; Almeida, GS; Kwok, C; Gravells, P; et al. (Impact Journals, LLC, 2020-06-09)This study investigates the influence expression of the MYCN oncogene has on the DNA damage response, replication fork progression and sensitivity to PARP inhibition in neuroblastoma. In a panel of neuroblastoma cell lines, ... -
Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway.
Conti, A; Majorini, MT; Elliott, R; Ashworth, A; Lord, CJ; et al. (IMPACT JOURNALS LLC, 2015-05-10)KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro-survival pathways, but it also triggers the trans-activation of pro-apoptotic ... -
Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers.
Khalique, S; Naidoo, K; Attygalle, AD; Kriplani, D; Daley, F; et al. (WILEY, 2018-07-20)ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ... -
Overexpression of MYB drives proliferation of CYLD-defective cylindroma cells.
Rajan, N; Andersson, MK; Sinclair, N; Fehr, A; Hodgson, K; et al. (WILEY-BLACKWELL, 2016-06-01)Cutaneous cylindroma is an adnexal tumour with apocrine differentiation. A predisposition to multiple cylindromas is seen in patients with Brooke-Spiegler syndrome, who carry germline mutations in the tumour suppressor ... -
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; et al. (AMER SOC CLINICAL INVESTIGATION INC, 2019-03-01)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 inhibitor combination therapy.
Dréan, A; Lord, CJ; Ashworth, A (ELSEVIER SCIENCE INC, 2016-12-01)In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with ... -
PARP Inhibitors - Trapped in a Toxic Love Affair.
Krastev, DB; Wicks, AJ; Lord, CJIt is often the case that when an investigational cancer drug first enters clinical development, its precise mechanism of action is unclear. This was the case for PARP inhibitors (PARPi) used to treat homologous ... -
PARP inhibitors and breast cancer: highlights and hang-ups
Pettitt, SJ; Lord, CJ (TAYLOR & FRANCIS LTD, 2018-01-01) -
PARP inhibitors: Synthetic lethality in the clinic.
Lord, CJ; Ashworth, A (AMER ASSOC ADVANCEMENT SCIENCE, 2017-03-17)PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors ...