Browsing Molecular Pathology by author "Pettitt, Stephen"
Now showing items 1-20 of 26
-
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 ... -
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 ... -
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), ... -
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 ... -
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 ... -
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 ... -
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 inhibitors and breast cancer: highlights and hang-ups
Pettitt, SJ; Lord, CJ (TAYLOR & FRANCIS LTD, 2018-01-01) -
Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.
Yap, TA; O'Carrigan, B; Penney, MS; Lim, JS; Brown, JS; et al. (AMER SOC CLINICAL ONCOLOGY, 2020-06-22)PURPOSE: Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging ...