Brian Dougherty

AstraZeneca (United States)

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Co-Authors

Zhongwu Lai

AstraZeneca (United States)

J. Carl Barrett

AstraZeneca (United States)

Charlie Gourley

Edinburgh Cancer Research

Daniel Stetson

AstraZeneca (United States)

Ruth March

AstraZeneca (United Kingdom)

Athena Matakidou

AstraZeneca (United Kingdom)

Jonathan R. Dry

AstraZeneca (United States)

Robert L. Hollis

Edinburgh Cancer Research

C. Simon Herrington

Edinburgh Cancer Research

Michael Churchman

Edinburgh Cancer Research

Cooperative Institutions

AstraZeneca (United Kingdom)

273

AstraZeneca (United States)

185

Harvard University

111

AstraZeneca (Brazil)

109

University of Cambridge

University College London

National Institutes of Health

Amgen (United States)

Memorial Sloan Kettering Cancer Center

Orano (United States)

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Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models

Cancer Research (2015)

Catherine A. Eberlein Daniel Stetson Aleksandra Markovets Katherine Al-Kadhimi Zhongwu Lai

Abstract Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. Cancer Res; 75(12); 2489–500. ©2015 AACR.

10.1158/0008-5472.can-14-3167

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Genetic Organization of Transposase Regions Surrounding bla _KPC Carbapenemase Genes on Plasmids from Klebsiella Strains Isolated in a New York City Hospital

Antimicrobial Agents and Chemotherapy (2009)

Thomas D. Gootz Mary Kay Lescoe Fadia B. Dib-Hajj Brian Dougherty Wen He

Carbapenem-resistant Klebsiella strains carrying Klebsiella pneumoniae carbapenemases (KPC) are endemic to New York City and are spreading across the United States and internationally. Recent studies have indicated that the KPC structural gene is located on a 10-kb plasmid-borne element designated Tn4401. Fourteen Klebsiella pneumoniae strains and one Klebsiella oxytoca strain isolated at a New York City hospital in 2005 carrying either bla(KPC-2) or bla(KPC-3) were examined for isoforms of Tn4401. Ten of the Klebsiella strains contained a 100-bp deletion in Tn4401, corresponding to the Tn4401a isoform. The presence of this deletion adjacent to the upstream promoter region of bla(KPC) in Tn4401a resulted in a different -35 promoter sequence of TGGAGA than that of CTGATT present in isoform Tn4401b. Complete sequencing of one plasmid carrying bla(KPC) from each of three nonclonal isolates indicated the presence of genes encoding other types of antibiotic resistance determinants. The 70.6-kb plasmid from K. pneumoniae strain S9 carrying bla(KPC-2) revealed two identical copies of Tn4401b inserted in an inverse fashion, but in this case, one of the elements disrupted a group II self-splicing intron. In K. pneumoniae strain S15, the Tn4401a element carrying bla(KPC-2) was found on both a large 120-kb plasmid and a smaller 24-kb plasmid. Pulsed-field gel electrophoresis results indicate that the isolates studied represent a heterogeneous group composed of unrelated as well as closely related Klebsiella strains. Our results suggest that endemic KPC-positive Klebsiella strains constitute a generally nonclonal population comprised of various alleles of bla(KPC) on several distinct plasmid genetic backgrounds. This study increases our understanding of the genetic composition of the evolving and expanding role of KPC-producing, healthcare-associated, gram-negative pathogens.

Strain (injury)

Insertion sequence

Klebsiella oxytoca

Klebsiella

10.1128/aac.01355-08

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Citations (159)

Data from Modeling RAS Phenotype in Colorectal Cancer Uncovers Novel Molecular Traits of RAS Dependency and Improves Prediction of Response to Targeted Agents in Patients

Justin Guinney Charles Ferté Jonathan R. Dry Robert McEwen Gilles Manceau

<div>AbstractPurpose: KRAS wild-type status is an imperfect predictor of sensitivity to anti-EGF receptor (EGFR) monoclonal antibodies in colorectal cancer, motivating efforts to identify novel molecular aberrations driving RAS. This study aimed to build a quantitative readout of RAS pathway activity to (i) uncover molecular surrogates of RAS activity specific to colorectal cancer, (ii) improve the prediction of cetuximab response in patients, and (iii) suggest new treatment strategies.Experimental Design: A model of RAS pathway activity was trained in a large colorectal cancer dataset and validated in three independent colorectal cancer patient datasets. Novel molecular traits were inferred from The Cancer Genome Atlas colorectal cancer data. The ability of the RAS model to predict resistance to cetuximab was tested in mouse xenografts and three independent patient cohorts. Drug sensitivity correlations between our model and large cell line compendiums were performed.Results: The performance of the RAS model was remarkably robust across three validation datasets. (i) Our model confirmed the heterogeneity of the RAS phenotype in KRAS wild-type patients, and suggests novel molecular traits driving its phenotype (e.g., MED12 loss, FBXW7 mutation, MAP2K4 mutation). (ii) It improved the prediction of response and progression-free survival (HR, 2.0; P < 0.01) to cetuximab compared with KRAS mutation (xenograft and patient cohorts). (iii) Our model consistently predicted sensitivity to MAP–ERK kinase (MEK) inhibitors (P < 0.01) in two cell panel screens.Conclusions: Modeling the RAS phenotype in colorectal cancer allows for the robust interrogation of RAS pathway activity across cell lines, xenografts, and patient cohorts. It demonstrates clinical utility in predicting response to anti-EGFR agents and MEK inhibitors. Clin Cancer Res; 20(1); 265–72. ©2013 AACR.</div>

10.1158/1078-0432.c.6521454

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Data from Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization

Stéphanie Lheureux Zhongwu Lai Brian Dougherty Sarah Runswick Darren Hodgson

<div>AbstractPurpose: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib.Experimental Design: A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo >2 years, ST as <3 months. Molecular analyses included germline BRCA1/2 status, three-biomarker homologous recombination deficiency (HRD) score, BRCA1 methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort.Results: Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (P < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (P < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with TP53, BRCA1, and BRCA2 mutations being most common (90%, 25%, and 35%, respectively). BRCA2 mutations were enriched among the LT responders. BRCA methylation was not associated with response duration. High myriad HRD score (>42) and/or BRCA1/2 mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and BRCA1/2 mutation.Conclusions: Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation. Clin Cancer Res; 23(15); 4086–94. ©2017 AACR.</div>

Olaparib

Serous ovarian cancer

10.1158/1078-0432.c.6527036

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Supplementary Data from Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance

Violeta Serra Anderson T. Wang Marta Castroviejo‐Bermejo Urszula M. Polanska Marta Palafox

Supplementary Data from Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance

Identification

PARP inhibitor

Wee1

10.1158/1078-0432.22489322

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Supplementary Data 1 from Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment

Mark Roschewski Manish R. Patel Patrick M. Reagan Nakhle S. Saba Graham P. Collins

Supplementary Data Supplementary Table 1: Key exclusion criteria Supplementary Table 2: Prior systemic therapies Supplementary Table 3: Subsequent anticancer therapy Supplementary Table 4: Mutations by response: cell-of-origin and genetic subtyping Supplementary Table 5: Representativeness of Study Participants Supplementary Figure 1: Study design Supplementary Figure 2: Plasma concentration of danvatirsen, acalabrutinib, and ACP-5862 (active metabolite of acalabrutinib) consistent with historical monotherapy data Supplementary Figure 3: EZB-related mutations by treatment response, number of cycles on treatment, cell-of-origin, and LymphGen cluster Supplementary Figure 4: STAT3 protein and ASO expression detection by IHC Supplementary Figure 5: Allele frequency over time for all patients by response Supplementary Figure 6: Copy number dynamics for all patients with available data by response Supplementary Figure 7: Peripheral blood analysis of gene expression associated with CD19+ B-cell signaling at baseline (A) and for baseline and longitudinal samples (B), and comparison of baseline gene expression of select B- and T-cell–specific genes in PBMCs in responders and nonresponders (C) Supplementary Figure 8: Peripheral blood analysis of gene expression associated with interferon-gamma signaling: baseline comparison (A) and baseline and longitudinal samples (B) Supplementary Figure 9: T-cell, B-cell, and NK-cell (TBNK) flow analysis: immunophenotyping in responders and nonresponders at baseline Supplementary Figure 10: Longitudinal immunophenotyping/immune cell population data (A) and percentage of CD4+ naïve T-cells among all CD4+ T cells (B) at each visit by treatment response Supplementary Figure 11: Pretreatment and on-treatment levels of cytokines/chemokines

Immunophenotyping

10.1158/1078-0432.23791929.v1

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Supplementary Data 1 from Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment

Mark Roschewski Manish R. Patel Patrick M. Reagan Nakhle S. Saba Graham P. Collins

Immunophenotyping

10.1158/1078-0432.24071555

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Impact of Kras Codon Sub-types In A Phase Ii Second-line Trial In Kras-mutant Advanced Non-small Cell Lung Cancer (nsclc) of Selumetinib Plus Docetaxel Versus Docetaxel Alone

Journal of Thoracic Oncology (2013)

Tom Liptrot Helen Mann I E Smith Gael McWalter Brian Dougherty

Selumetinib

Source

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Peer Review #2 of "Prioritisation of structural variant calls in cancer genomes (v0.2)"

Miika Ahdesmäki Brad Chapman Pablo Cingolani Oliver Hofmann Aleksandr Sidoruk

Sensitivity of short read DNA-sequencing for gene fusion detection is improving, but is hampered by the significant amount of noise composed of uninteresting or false positive hits in the data.In this paper we describe a tiered prioritisation approach to extract high impact gene fusion events from existing structural variant calls.Using cell line and patient DNA sequence data we improve the annotation and interpretation of structural variant calls to best highlight likely cancer driving fusions.We also considerably improve on the automated visualisation of the high impact structural variants to highlight the effects of the variants on the resulting transcripts.The resulting framework greatly improves on readily detecting clinically actionable structural variants.

10.7287/peerj.3166v0.2/reviews/2

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Antitumor activity of the WEE1 inhibitor AZD1775 as a monotherapy and in combination with the PARP inhibitor olaparib in patient-derived explant (PDX) models

European Journal of Cancer (2016)

M.J. O’Connor Rajesh Odedra Sangeetha Palakurthi Andrew Hughes Zhongwu Lai

Olaparib

PARP inhibitor

Wee1

10.1016/s0959-8049(16)33023-4

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Citations (3)