Browsing by author "Pettitt, Stephen"
Now showing items 1-20 of 35
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ATR Is a Therapeutic Target in Synovial Sarcoma.
Jones, SE; Fleuren, EDG; Frankum, J; Konde, A; Williamson, CT; et al. (AMER ASSOC CANCER RESEARCH, 2017-12-15)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; et al. (AMER ASSOC CANCER RESEARCH, 2021-11-01)PARP inhibitors are approved for treating advanced prostate cancers (APC) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed ... -
Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7.
Baxter, JS; Brough, R; Krastev, DB; Song, F; Sridhar, S; et al. (WILEY, 2023-10-22)The F-box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate-recognition subunit of Skp, cullin, F-box (SCF)-containing complexes. The tumour-suppressive role of FBXW7 is ascribed to its ... -
Chemosensitivity profiling of osteosarcoma tumour cell lines identifies a model of BRCAness.
Holme, H; Gulati, A; Brough, R; Fleuren, EDG; Bajrami, I; et al. (NATURE PORTFOLIO, 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 BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance.
Pettitt, SJ; Frankum, JR; Punta, M; Lise, S; Alexander, J; et al. (AMER ASSOC CANCER RESEARCH, 2020-10-01)Reversion mutations in BRCA1 or BRCA2 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 reversions. This ... -
Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets.
Krastev, DB; Pettitt, SJ; Campbell, J; Song, F; Tanos, BE; et al. (NATURE PUBLISHING GROUP, 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 ... -
Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.
Hewitt, G; Borel, V; Segura-Bayona, S; Takaki, T; Ruis, P; et al. (CELL PRESS, 2021-02-18)Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair ... -
Dissecting PARP inhibitor resistance with functional genomics.
Pettitt, SJ; Lord, CJ (CURRENT BIOLOGY LTD, 2019-02-01)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; et al. (AMER ASSOC CANCER RESEARCH, 2018-04-01)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; et al. (NATURE PUBLISHING GROUP, 2017-06-27)BACKGROUND: 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 ... -
Elucidating Prostate Cancer Behaviour During Treatment via Low-pass Whole-genome Sequencing of Circulating Tumour DNA.
Sumanasuriya, S; Seed, G; Parr, H; Christova, R; Pope, L; et al. (ELSEVIER, 2021-08-01)BACKGROUND: Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises normal and ... -
Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
Baxter, JS; Johnson, N; Tomczyk, K; Gillespie, A; Maguire, S; et al. (CELL PRESS, 2021-07-01)A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), ... -
Functional screening reveals HORMAD1-driven gene dependencies associated with translesion synthesis and replication stress tolerance.
Tarantino, D; Walker, C; Weekes, D; Pemberton, H; Davidson, K; et al. (SPRINGERNATURE, 2022-08-05)HORMAD1 expression is usually restricted to germline cells, but it becomes mis-expressed in epithelial cells in ~60% of triple-negative breast cancers (TNBCs), where it is associated with elevated genomic instability (1). ... -
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 ... -
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 ... -
A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant.
Pettitt, SJ; Shao, N; Zatreanu, D; Frankum, J; Bajrami, I; et al. (SPRINGERNATURE, 2023-09-01)Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, ... -
Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance.
Serra, V; Wang, AT; Castroviejo-Bermejo, M; Polanska, UM; Palafox, M; et al. (AMER ASSOC CANCER RESEARCH, 2022-10-14)PURPOSE: PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance ... -
Identification of genes that promote PI3K pathway activation and prostate tumour formation.
Francis, JC; Capper, A; Rust, AG; Ferro, K; Ning, J; et al. (SPRINGERNATURE, 2024-06-10)We have performed a functional in vivo mutagenesis screen to identify genes that, when altered, cooperate with a heterozygous Pten mutation to promote prostate tumour formation. Two genes, Bzw2 and Eif5a2, which have been ... -
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 ...